Enhancement of antimicrobial silver, silver coatings, or silver platings

ABSTRACT

Antimicrobial metal ion coatings. In particular, described herein are coatings including an anodic metal (e.g., silver and/or zinc and/or copper) that is co-deposited with a cathodic metal (e.g., palladium, platinum, gold, molybdenum, titanium, iridium, osmium, niobium or rhenium) on a substrate (including, but not limited to absorbable/resorbable substrates) so that the anodic metal is galvanically released as antimicrobial ions when the apparatus is exposed to a bodily fluid. The anodic metal may be at least about 25 percent by volume of the coating, resulting in a network of anodic metal with less than 20% of the anodic metal in the coating fully encapsulated by cathodic metal.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application claims priority to U.S. Provisional PatentApplication No. 62/123,339, filed Nov. 14, 2014, titled “CREATION OFANTIMICROBIAL AGENT ON SILVER, SILVER COATING, OR PLATING VIA EXPOSUREOF THE SILVER TO OZONE” which is herein incorporated by reference in itsentirety.

This patent may also be related to U.S. patent application Ser. No.1/679,893, filed on Apr. 6, 2015, titled “COATINGS FOR THE CONTROLLABLERELEASE OF ANTIMICROBIAL METAL IONS,” which claims priority as acontinuation-in-part to U.S. patent application Ser. No. 14/569,545,filed on Dec. 12, 2014, now U.S. Pat. No. 8,999,367, and titled“BIOABSORBABLE SUBSTRATES AND SYSTEMS THAT CONTROLLABLY RELEASEANTIMICROBIAL METAL IONS,” which is a continuation of U.S. patentapplication Ser. No. 14/302,352, filed on Jun. 11, 2014 and titled“BIOABSORBABLE SUBSTRATES AND SYSTEMS THAT CONTROLLABLY RELEASEANTIMICROBIAL METAL IONS,” now U.S. Pat. No. 8,927,004, and U.S.Provisional Patent Application No. 62/059,714, filed on Oct. 3, 2014 andtitled “COATINGS FOR THE CONTROLLABLE RELEASE OF ANTIMICROBIAL METALIONS.” Each of these patents and patent applications is hereinincorporated by reference in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

FIELD

Described herein are substrates having antimicrobial metal ion coatingsthat are treated with ozone to enhance their antimicrobial properties.In particular, described herein are substrates that are coated with ananodic metal such as silver that is co-deposited with a cathodic metal(e.g., palladium, platinum, gold, molybdenum, titanium, iridium, osmium,niobium or rhenium) on the substrate to form a continuous path ofinterconnected veins of (e.g., silver) metal within the matrix ofcathodic metal or a continuous path of interconnected veins of cathodicmetal within the matrix of anodic metal, wherein the continuous pathextends from an outer surface of the coating to the substrate; thesecoatings may then be treated with ozone to remove biologic materialprior to sterilization and to greatly enhance the antimicrobialproperties of silver/cathodic coating. Other oxidizing agents (e.g.,peroxide, etc.) may be used in alternatively or in addition to ozone.Thus, in addition to the galvanic released of antimicrobial silver asantimicrobial ions (e.g., when the coated substrates is contacted by aconductive fluid environment, including when inserted into a subject'sbody), the ozonation may further enhance the antimicrobial effects ofjust galvanically released silver alone.

BACKGROUND

Antimicrobial or antibiotic agents are widely used to treat as well asto prevent infection. In particular, silver is known to be antimicrobialand has been used (primarily as a coating) in various medical deviceswith limited success. Both active (e.g., by application of electricalcurrent) and passive (e.g., galvanic) release of silver ions have beenproposed for use in the treatment and prevention of infection. However,the use of silver-releasing implants have been limited because of thedifficulty in controlling and distributing the release of silver ions aswell as the difficulty in maintaining a therapeutically relevantconcentration of silver ions in an appropriate body region. Zinc sharesmany of the same antimicrobial properties of silver, but has been lesscommonly used, and thus even less is known about how to control theamount and distribution of the release of silver ions to treat and/orprevent infection.

In addition, ozone (O₃) by itself has been known to act as anantimicrobial agent. For example, ozonated water has been used as astrong antimicrobial agent against foodborne pathogens. Althoughcombinations of ozone and antimicrobial ions such as silver have beensuggested (see., e.g., Kang S-N, et al., “Effect of a Combination of LowLevel Ozone and Metal Ions on Reducing Escherichia coli O157:H7 andListeria monocytogenes” Molecules 2013, 18, 4018-4025), such an approachhas suggested only the addition of ozone in a solution alreadycontaining silver ions. Pre-treatment of “dry” sources of antimicrobialions (including silver coatings) has not previously been suggested, asthe proposed, and previous experiments have assumed that ozone must beapplied concurrently with silver ion treatment, which is impractical inmany instances where it would be useful to provide for the release ofantimicrobial ions.

For example, it would be highly beneficial to use an antimicrobial agentsuch as silver and/or zinc as part of an implant, including abioabsorbable implant, in part because the risk of acquiring infectionsfrom bioabsorbable materials in medical devices is very high. Manymedical applications exist for bioabsorbable materials including: woundclosure (e.g., sutures, staples, adhesives), tissue repair (e.g.,meshes, such as for hernia repair), prosthetic devices (e.g., internalbone fixation devices, etc.), tissue engineering (e.g., engineered bloodvessels, skin, bone, cartilage, liver, etc.) and controlled drugdelivery systems (such as microcapsules and ion-exchange resins). Theuse of bioabsorbable materials in medical applications such as these mayreduce tissue or cellular irritation and the induction of aninflammatory response.

Bioabsorbable materials for medical applications are well known. Forexample, synthetic bioabsorbable polymers may includepolyesters/polylactones such as polymers of polyglycolic acid,glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc.,polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, andcopolymers of these and related polymers or monomers, as well asnaturally derived polymers such as albumin, fibrin, collagen, elastin,chitosan, alginates, hyaluronic acid; and biosynthetic polyesters (e.g.,3-hydroxybutyrate polymers). However, like other biomaterials,bioabsorbable materials are also subjected to bacterial contaminationand can be a source of infections which are difficult to control. Thoseinfections quite often require their removal and costly antimicrobialtreatments.

Efforts to render bioabsorbable materials more infection resistantgenerally have focused on impregnating the materials with antibiotics orsalts such as silver salts, and have provided only limited andinstantaneous antimicrobial activity. It is desirable to have anantimicrobial effect which is sustained over time, such that theantimicrobial effect can be prolonged for the time that thebioabsorbable material is in place. This can range from hours or days,to weeks or even years.

Further, although antimicrobial/antibacterial metal coatings on medicaldevices have been suggested, metal coatings (such as silver or coppercoatings) have not been characterized or optimized. In suchapplications, it is important that the metal coatings do not shed orleave behind large metal particulates in the body, which may induceunwanted immune responses and/or toxic effects. Further, it is essentialthat the release of the antimicrobial agent (metal) be metered over thelifetime of the implant.

For example, U.S. Pat. No. 8,309,216 describes substrates includingdegradable polymers that include an electron donor layer (such assilver, copper or zinc) onto which particles of palladium and platinum,plus one other secondary metal (chosen from gold, ruthenium, rhodium,osmium, iridium, or platinum) are deposited onto. Although suchmaterials are described for anti-microbial implants (e.g., pacemakers,etc.), the separate layers formed by this method would be problematicfor antimicrobial coatings in which the undercoating of silver, copperor zinc were being released, potentially undermining the platinum andsecondary metal.

Similarly, U.S. Pat. No. 6,719,987 describes bioabsorbable materialshaving an antimicrobial metal (e.g., silver) coating that can be usedfor an implant. The silver coating is for release of particles(including ions) and must be in a crystalline form characterized bysufficient atomic disorder. In this example, the silver is alsodeposited in one or more layers. U.S. Pat. No. 6,080,490 also describesmedical devices with antimicrobial surfaces that are formed by layers ofmetals (e.g., silver and platinum) to release ions; layers are etched toexpose regions for release. The outer layer is always Palladium (and oneother metal), beneath which is the silver.

Thus, it would be highly desirable to provide devices, systems andmethods for the controlled release (particularly the controlled galvanicrelease) of a high level of silver, zinc or silver and zinc ions from abioabsorbable material into the tissue for a sufficient period of timeto treat or prevent infection.

Known systems and devices, including those described above, that haveattempted to use ions (e.g., silver and/or zinc) on bioabsorbablematerials to treat infection have suffered from problems such as:insufficient amounts of ions released (e.g., ion concentration was toolow to be effective); insufficient time for treatment (e.g., the levelsof ions in the body or body region were not sustained for a long enoughperiod of time); and insufficient region or volume of tissue in whichthe ion concentration was elevated (e.g., the therapeutic region was toosmall or limited, such as just on the surface of a device). Further, theuse of galvanic release has generally been avoided or limited because itmay effectively corrode the metals involved, and such corrosion isgenerally considered an undesirable process, particularly in a medicaldevice.

There is a need for antimicrobial coatings for substrates generally, andmore specifically, there is a need for highly effective (“enhanced”)coatings that provide a high level of antimicrobial activity.Antimicrobial coatings (and particularly the ozone-enhanced coatingsdescribed herein) may be useful for any surface that will be exposed toa conductive fluid, including blood, sweat, lymph, etc., whetherimplanted or not. For example, there is a particular need forantimicrobial coatings for bioabsorbable materials, which can create aneffective and sustainable antimicrobial effect, which do not interferewith the bioabsorption of the bioabsorbable material, and which do notshed or leave behind large metal particulates in the body as thebioabsorbable material disappears.

Therapeutically, the level of silver and/or zinc ions released into abody is important, because it may determine how effective theantimicrobial ions are for treating or preventing infection. Asdescribed in greater detail below, the amount or ions releasedgalvanically may depend on a number of factors which have not previouslybeen well controlled. For example, galvanic release may be related tothe ratio of the anode to the cathode (and thus, the driving force) aswell as the level of oxygen available; given the galvanic reaction, thelevel of oxygen may be particularly important for at the cathode.Insufficient oxygen at the cathode may be rate-limiting for galvanicrelease.

For example, with respect to silver, it has been reported that aconcentration of 1 mg/liter of silver ions can kill common bacteria in asolution. Silver ions may be generated a galvanic system with silver asthe anode and platinum or other noble metal as the cathode. However oneof the challenges in designing a galvanic system for creation of silverion in the body that has not been adequately addressed is theappropriate ratios of the areas of the electrodes (e.g., anode tocathode areas) in order to create the germicidal level of free silverions.

Thus, to address the problems and deficiencies in the prior artmentioned above, described herein are systems, methods and devices (andin particular coatings, methods of coatings) for substrates thatcontrollably release antimicrobial metal ions, including apparatuses(e.g., devices and/or systems) and methods for prevent infection and foreliminating existing infections, in which the antimicrobial coating hasbe treated with ozone (resulting in an ozone-treated or enhancedcoating) having superior antimicrobial activity. The enhanced coatingsdescribed herein may be used as part of any appropriate substrate,including medical devices (both implanted, inserted, andnon-implanted/inserted medical devices), and non-medical devicesincluding hand-held articles. In some particular examples, describedbelow are implants including bioabsorbable substrates, and methods forusing them.

SUMMARY OF THE DISCLOSURE

In general, described herein are ozone-enhanced antimicrobial coatingsand methods of forming and using such ozone-enhanced coatings for anysubstrate that will come into contact with a bodily fluid and/orsecretion, in which the coating may galvanically release antimicrobialions. These enhanced coatings are configured so that the release of theantimicrobial ions is sustained over a predetermined time period ofcontinuous or intermittent exposure to the bodily fluid, and further sothat the amount and/or concentration of the antimicrobial ions releasedis above a predetermined threshold for effective antimicrobial effecteither locally or within a region exposed to the coating.

Treatment of antimicrobial metals (e.g., anionic metals such silver,nickel, etc.) and in particular the silver/cathodic metal co-coatingsdescribed herein, with ozone will result in an ozonated metal (e.g.,ozonated silver, ozonated silver ion) surface. An ozonated metal (e.g.,ozonated silver) surface may be any metal surface that has been treatedby the application of ozone gas, as described herein, resulting in amodification of the anodic metal (e.g., silver). The modification may bedetectable both chemically and empirically, based on the enhancement ofthe antimicrobial effect (e.g., a greater than 30%, 40%, 50%, 60%, 70%,80%, 100%, etc., increase in the region of antimicrobial activitycompared to non-enhanced anodic metal. Without being bound by aparticular theory of effect or operation, these enhanced anodic (andparticularly co-deposited silver/cathodic coatings) surfaces have a muchlarger observable antimicrobial effect, which is sustained over manyhours, days, weeks and months, compared to untreated surfaces. Forexample, ozone treatment of silver and/or silver/cathodic co-depositedsurfaces may result in the formation of Ag₄O₄. The Ag₄O₄ maybe on theouter surface and/or may penetrate somewhat into the coating (e.g., maybe more concentrated towards the outer surface). Although the exactnature of the modification of the ozone-treated antimicrobial surfacesdescribed herein may be more complicated, the effects are striking.Pre-treatment of even a simple silver surface (e.g., compared tosurfaces including the co-deposited silver/cathodic metals describedherein) may result in a greater than 50% (or in most cases more, e.g.,2×, 3×, 4×, etc.) enhancement of the antimicrobial activity when assayedas described herein. However, pre-treatment (e.g., for greater than 5min, greater than 10 min, greater than 15 min) of a coating comprisingco-depositions of an anodic metal (e.g., one or more of zinc, silver,and/or copper) and a cathodic metal (e.g., one or more of: palladium,platinum, gold, molybdenum, titanium, iridium, osmium, niobium andrhenium) as described herein may enhance the already high antimicrobialeffects seen with these coatings.

Although particular attention and examples of types of substrates, suchas medical devices, and in particular implantable medical deviceincluding bioabsorbable substrates, it should be readily understood thatthe coatings described herein may be used on any substrate surface thatwill come into contact with bodily fluids which would benefit from anantimicrobial effect, including devices that are not inserted orimplanted into a body. Bodily fluids are generally electricallyconductive, and may include any of: blood, blood serum, amniotic fluid,aqueous humor, vitreous humor, bile, breast milk, cerebrospinal fluid,cerumen, chyle, chyme, endolymph, perilymph, exudates, feces (diarrhea),female ejaculate, gastric acid, gastric juice, lymph, mucus (includingnasal drainage and phlegm), pericardial fluid, peritoneal fluid, pleuralfluid, pus, rheum, saliva, sebum, semen, sputum, synovial fluid, sweat,tears, urine, vaginal secretion, vomit, etc.

As used herein, a substrate may be any surface onto which the coatingmay be applied, which may be any appropriate material, including, butnot limited to metals (e.g., alloys, etc.), ceramics, stone, polymers,wood, glass, etc., including combinations of materials. In somevariations the surface of the substrate may be prepared before thecoating is applied, as described herein. The substrate may be rigid orflexible. In particular, the coatings described herein may be applied toflexible and/or fiber-like materials such as strings, sutures, wovenmaterials, thin electrical leads, and the like. As described in greaterdetail herein, the coating typically does not inhibit the flexibility,pliability, bendability, etc. of the substrate material.

For example, described herein are methods of forming an enhancedantimicrobial surface comprising: coating a substrate surface with asilver material; and applying ozone to the coated surface for at least 1minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, atleast 5 minutes, etc., including preferably at least 5 minutes.

Any silver material may be used, including pure silver (metallicsilver), or in particular, silver coatings including co-depositions ofsilver and a cathodic metal to drive galvanic release of the silver.This coating may be any of the coatings described herein.

For example a method of forming an enhanced antimicrobial surface mayinclude: co-depositing a coating of silver and a cathodic metal onto asubstrate surface, wherein the co-deposited coating comprises a mixtureof between about 25% and 75% by volume of silver, and between about 25%to 75% by volume of the cathodic metal; and applying ozone to the coatedsurface for at least 1 minute, at least 2 minutes, at least 3 minutes,at least 4 minutes, at least 5 minutes, etc., including preferably atleast 5 minutes.

Any of the methods of applying a coating described herein may includepreparing the surface. In particular, the method may include preparingthe surface by treating it with a noble gas (such as argon) to removeany impurities, oxides, or the like. In some variations, this mayinvolve applying the noble gas (which may include a charged noble gas)under pressure (e.g., blasting) against the surface. In some variationsthe method may include blasting the substrate surface with a noble gasbefore applying the silver material. The method of preparing by forcinga noble gas such as argon (e.g., charged argon) against the surface maybe used in place of applying an additional adhesive layer. Surprisingly,the applicants have found that cleaning and preparing the surface withargon may alleviate the need for the application of an additionaladhesion layer when the surface is made, for example, of a nickeltitanium material. For example, any of these methods may include a stepof preparing the surface by forcing a jet of argon (e.g., blasting thesubstrate surface with argon and/or charged argon, plasma, etc.) beforeapplying the silver metal.

As mentioned, the silver coating may be a layer or coating of silverthat is co-deposited with a cathodic metal. For example, coating mayinclude coating the substrate surface with a coating comprising amixture of between about 25% and 75% by volume of silver, and betweenabout 25% to 75% by volume of a cathodic metal co-deposited on thesubstrate, e.g., so that the coating comprises a plurality ofmicroregions or microdomains of the silver in a matrix of cathodic metalor a plurality of microregions or microdomains of cathodic metal in amatrix of silver, the microregions or microdomains forming a continuouspath of interconnected veins of silver through the coating thickness, ora continuous path of interconnected veins of cathodic metal through thecoating thickness, wherein the continuous path extends from an outersurface of the coating through the coating to an opposite side of thecoating.

Ozonation, or the application of ozone on the surface for apredetermined time to modify the surface, may be generally performed by,e.g., directing a jet of ozone against the surface for the predefinedtime. For example, ozonation may include applying ozone to the coatedsurface for at least 5 minutes, at least 10 minutes, at least 15 min, atleast 20 min, at least 25 min, etc. The longer the application of ozoneto/against the surface, the greater the resulting ozonation, which mayin turn more effectively enhance the antimicrobial effects, asillustrated herein. For example, applying the ozone may comprisespraying the surface with a jet comprising ozone.

Also described herein are methods of galvanically releasingantimicrobial ions to form an antimicrobial zone around a surface of asubstrate, the method comprising: contacting the surface with aconductive fluid, wherein the surface comprises a coating comprising amixture of between about 25% and 75% by volume of silver, and betweenabout 25% to 75% by volume of a cathodic metal co-deposited on thesubstrate, further wherein the coating has been ozonized by theapplication of ozone to the surface for at least 5 minutes; andgalvanically releasing antimicrobial ions of the anodic metal from thecoating. As mentioned above, the coating may comprise a plurality ofmicroregions or microdomains of the silver in a matrix of cathodic metalor a plurality of microregions or microdomains of cathodic metal in amatrix of silver, the microregions or microdomains forming a continuouspath of interconnected veins of silver through the coating thickness, ora continuous path of interconnected veins of cathodic metal through thecoating thickness, wherein the continuous path extends from an outersurface of the coating through the coating to an opposite side of thecoating.

Also described herein are apparatuses that include ozonated silvercoatings (or outer surfaces) that have enhanced antimicrobial activity.For example, an apparatus that galvanically releases antimicrobial ionsmay include: a substrate surface; and an ozonated coating on the outersubstrate surface, the ozonated coating comprising a mixture of betweenabout 25% and 75% by volume of silver, and between about 25% to 75% byvolume of a cathodic metal co-deposited on the substrate surface, sothat there is a continuous path of silver from the surface to the outersubstrate surface.

An apparatus that galvanically releases antimicrobial ions having anenhanced antimicrobial surface may include: a substrate surface; and anozonated coating on the outer substrate surface, the ozonated coatingcomprising a mixture of between about 25% and 75% by volume of silver,and between about 25% to 75% by volume of a cathodic metal co-depositedon the substrate surface, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains forming acontinuous path of interconnected veins of anodic metal through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating through the coating toan opposite side of the coating. The ozonated coating may compriseoxides of silver (e.g., Ag₄O₄).

In any of the ozonated coating described herein, less than 30% of thesilver may be fully encapsulated within the matrix of cathodic metal andconnects through a microregion or microdomain of silver to the outersurface of the coating. For example, less than 20% of the silver may befully encapsulated within the matrix of cathodic metal and connectsthrough a microregion or microdomain of silver to the outer surface ofthe coating.

In any of the methods and apparatuses described herein the cathodicmetal may comprises one or more of: palladium, platinum, or gold. In anyof these methods and apparatuses, the cathodic metal may be one or moreof: palladium, platinum, gold, molybdenum, titanium, iridium, osmium,niobium and rhenium.

Any substrate may be used. For example, the coating may comprise thesilver and the cathodic metal that have been vapor-deposited onto thelength of a filament so that the silver is not encapsulated by thecathodic metal. The substrate surface may be an outer surface of one of:a pacemaker, defibrillator, neurostimulator, or ophthalmic implant. Thesubstrate surface may be an outer surface of one of: an implantableshunt, an artificial joint, a hip implant, a knee implant, a catheter, astent, an implantable coil, a pump, an intrauterine device (IUD), aheart valve, a surgical fastener, a surgical staple, a surgical pin, asurgical screw, a suture (e.g., surgical suture material, or othersuture), an implantable electrical lead, or an implantable plate. Thesubstrate surface may be an outer surface of one of: a retractor, abariatric balloon, an orthodontic brace, a breast implant, a surgicalsponge, a gauze, a mesh pouch (e.g., mesh envelope) or a wound packingmaterial. For example, the substrate may be a bioabsorbable filament,such as one or more of: polylactic acid (PLA), poly(lactic-co-glycolicacid) (PLGA), polyglycolide (PGA), polyglycolide-co-trimethylenecarbonate (PGTMC), poly(caprolactone-co-glycoside), poly(dioxanone)(PDS), and poly(caprolactone) (PCL).

In any of the methods and apparatuses described herein, the coating maybe fractured (e.g., to increase the surface area), as described herein.The coating may be fractured so that a surface area of the coating isincreased by at least 25% compared to the surface area of the coating inan unfractured state.

In general, any of the galvanic release coatings or surfaces describedherein may be ozonated (e.g., treated with ozone), which may enhancetheir antimicrobial effects. Further any of the methods of forming acoating described herein may include a step of enhancing theantimicrobial effect of the coating by treating with ozone, as discussedabove. Finally, any of the methods of galvanically releasing ozone mayinclude treating or using an ozone-treated layer.

The coatings described herein typically include co-depositions of ananodic metal (e.g., one or more of zinc, silver, and/or copper) and acathodic metal (e.g., one or more of: palladium, platinum, gold,molybdenum, titanium, iridium, osmium, niobium and rhenium). In somecases, the anodic metal is silver, or silver and an additional anodicmetal. In particular, the ozone-treated surfaces described herein mayinclude silver as the anodic metal. The anodic and cathodic material inthe coating are non-uniformly dispersed within the coating, so thatthere are veins (e.g., microdomains or microregions, such as clusters,clumps, etc.) of anodic metal within a matrix of cathodic metal and/orveins of cathodic metal within a matrix of anodic metal. The relativeamounts of anodic metal in the coating may be between 20% and 80% byvolume, or more preferably between 25% and 75% by volume, or morepreferably still, between 30% and 70% by volume (e.g., greater than 20%,greater than 25%, greater than 30%, etc.).

The anodic metal within the coating typically forms a continuous paththrough the coating (extending from the outer surface of the coating allthe way to the base of the coating, which may be the portion against thesubstrate), so that all or most all (e.g., greater than 80%, greaterthan 85%, greater than 90%, greater than 95%, greater than 96%, greaterthan 97%, greater than 98%, greater than 99%, etc.) of the anodic metalin the coating is interconnected, preventing entrapment of a substantialportion of the anodic metal within the coating. Similarly, the cathodicmetal within the coating may be in continuous contact throughout thecoating layer (extending from the outer surface of the coating all theway to the base of the coating, which may be the portion against thesubstrate) so that all or most all (e.g., greater than 80%, greater than85%, greater than 90%, greater than 95%, greater than 96%, greater than97%, greater than 98%, greater than 99%, etc.) of the cathodic metal inthe coating is interconnected.

As mentioned, the coatings described herein may be applied to anyappropriate substrate. For example, an apparatus that galvanicallyreleases antimicrobial ions may include: a substrate; and a coating onthe substrate comprising an anodic metal (that has been co-depositedwith a cathodic metal on the substrate) to form a non-uniform mixture ofthe anodic and cathodic metals, wherein the coating comprises aplurality of microregions or microdomains of anodic metal in a matrix ofcathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of anodic metal, the microregions ormicrodomains forming a continuous path of interconnected veins of anodicmetal within the matrix of cathodic metal or a continuous path ofinterconnected veins of cathodic metal within the matrix of anodicmetal, wherein the continuous path extends from an outer surface of thecoating to the substrate; further wherein the anodic metal isgalvanically released as antimicrobial ions when the apparatus isinserted into a subject's body.

The substrate may be an implant configured to be inserted into a humanbody, including a medical device. The substrate may be device configuredto be temporarily or permanently inserted into the body (e.g., surgicaltools, implants, etc.). In some variations the substrate may be a deviceconfigured to be worn on a human body (e.g., jewelry, clothing, surgicalgowns, masks, gloves, etc.). The substrate may be a structure configuredto hold, support and/or house a subject (e.g., gurney, chair, bed,etc.). The coating may be applied to all or a portion of the substrate,particularly those surfaces of the substrate that may be placed incontact with a bodily fluid (e.g., a handle, supporting surface, etc.).The substrate may be a household item, such as a cutlery (e.g., spoons,baby spoons, forks, etc.), food handling items (e.g., platters, plates,straws, cups, etc.), handles (e.g., doorknobs, pushes, etc.), faucets,drains, tubs, toilets, toilet knobs, light switches, etc.

The anodic metal may be any combination of the anodic metals describedherein (e.g., zinc, silver, copper, both zinc and silver, etc.). Theanodic metal may be least about 30 percent by volume (or in somevariations, by weight, e.g., when the densities of anodic and cathodicmaterials are similar) of the coating.

The cathodic metal may generally have a higher galvanic potential thanthe anodic metal. This may drive the galvanic (e.g., “corrosion”) of theanodic metal when the coating is exposed to a bodily fluid. For example,the cathodic metal may comprise one or more of: palladium, platinum,gold, molybdenum, titanium, iridium, osmium, niobium and rhenium.

The coating may be formed by vapor deposition. For example, the anodicmetal and the cathodic metal may have been vapor-deposited onto thesubstrate so that the anodic metal is not encapsulated by the cathodicmetal, e.g., so that the anodic metal (and/or in some variations thecathodic metal) include veins that extend continuously through thecoating from the outer surface to the base (e.g., the “bottom” of thecoating adjacent to the substrate) of the coating. Thus, the continuouspath of interconnected veins may be interconnected so that less than 15%of the anodic metal is completely encapsulated within the matrix ofcathodic metal, or less than 15% of the cathodic metal is completelyencapsulated within the matrix of anodic metal. The continuous path ofinterconnected veins may be interconnected so that less than 10% of theanodic metal is completely encapsulated within the matrix of cathodicmetal, or less than 10% of the cathodic metal is completely encapsulatedwithin the matrix of anodic metal.

An apparatus that galvanically releases antimicrobial ions may include:a substrate; and an ozonated coating on the substrate comprising zincand silver and a cathodic metal that are all co-deposited onto thesubstrate, wherein the zinc and silver are at least about 25 percent byvolume (or in some variations by weight) of the coating and form anon-uniform mixture of the zinc and the cathodic metal and a non-uniformmixture of the silver and the cathodic metal, wherein the coatingcomprises a plurality of microregions or microdomains of zinc and silverin a matrix of cathodic metal or a plurality of microregions ormicrodomains of cathodic metal in a matrix of zinc and a matrix ofsilver, the microregions or microdomains forming a continuous path ofinterconnected veins of zinc and silver within the matrix of cathodicmetal or a continuous path of interconnected veins of cathodic metalwithin the matrix of zinc and the matrix of silver, wherein thecontinuous paths extend from an outer surface of the substrate; furtherwherein the zinc and silver are galvanically released as antimicrobialions when the apparatus is inserted into a subject's body.

In some variations, the substrate may be bio-absorbable. For example, insome variations, the substrate is configured to degrade within the bodyto form a degradation product including an anion that complexes withions of the anodic metal and diffuses into the subject's body to form anantimicrobial zone. For example, a bioabsorbable apparatus thatgalvanically releases antimicrobial ions may include: an implant havingan outer surface comprising a substrate; and an ozonated coating on thesubstrate comprising an anodic metal that is co-deposited with acathodic metal on the substrate to form a non-uniform mixture of theanodic and cathodic metals, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains formingcontinuous paths of interconnected veins of anodic metal within thematrix of cathodic metal or continuous paths of interconnected veins ofcathodic metal within the matrix of anodic metal, wherein the continuouspaths extend from an outer surface of the coating to the substrate;further wherein the anodic metal is galvanically released asantimicrobial ions when the apparatus is inserted into a subject's body.

Thus, also described herein are bioabsorbable substrates, andparticularly bioabsorbable filaments, that galvanically releaseantimicrobial ions. The bioabsorbable filament is coated with an anodicmetal (such as silver, copper and/or zinc) that has been co-depositedwith a cathodic metal (such as platinum, gold, palladium) along at leasta portion of the length of the filament. The filament retains itsflexibility. After insertion into the body, the anodic metal corrodes asthe filament is bioabsorbed. The degradation of the filament may createa local pH that enhances the release of the silver and/or copper and/orzinc ions.

In general, the coated filaments may be arranged into structures (e.g.,sutures, mesh, slings, yarns, etc.) that can be implanted into the body.

As mentioned, the anodic and cathodic metals forming the coatingsdescribed herein are typically co-deposited together, and not coated inlayers (e.g., atop each other). For example, the metals may be jointlyvapor deposited. Examples of jointly deposited anodic and cathodicmaterials include silver-platinum, copper-platinum, zinc-platinum,silver-gold, copper-gold, zinc-gold, etc. Different types of jointlydeposited anodic and cathodic metals may be arranged on the bioabsorblesubstrate. For example, silver-platinum may be coated near (either nottouching or touching) a region of zinc-platinum; different co-depositedanodic/cathodic metals may be a spacer region on the substrate.

In some variations, described herein are devices and methods forpreventing an infection in an implantable device such as a pacemaker ora defibrillator when inserting it into a body by incorporatingbioabsorbable materials that galvanically releaseantimicrobial/antibacterial metals such as silver and/or zinc and/orcopper. For example, an implant may be inserted into a woven mesh madeof a bioabsorbable material that is coated (or impregnated) with ananti-microbial anodic metal ions such as silver or zinc co-depositedwith a catalytic cathodic metal such as platinum, gold, or palladium.

In general, as mentioned above, the anodic metal may be silver, zinc, orany other metal with germicidal activity, and the cathode metal may beplatinum, gold, palladium, or any other metal with catalytic action,including molybdenum, titanium, iridium, osmium, niobium and rhenium.The biodegradable substrate may be a biodegradable filament, such aspolylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA),polyglycolide (PGA), polyglycoside-co-trimethylene carbonate (PGTMC),poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), andpoly(caprolactone) (PCL). As used herein the terms biodegradable andbioabsorbable may be used interchangeably.

For example, described herein are biodegradable filaments that may beformed into an envelope, pouch, pocket, etc. (generically, aco-implantable structure) made of a biodegradable polymer (such as PLGA,PGA, PLA, polycaprolactone, etc.). The implant may be co-implanted withthe co-implantable structure, for example, by placing the mesh onto theimplant before, during or after insertion into the body. Theco-deposited metal coating of the co-implantable structure creates agalvanic system resulting in release of germicidal ions protecting thedevice from getting infected in the body once the device is implantedwith the structure into a body. In the semi-aqueous environment of thebody, the metal will corrode over time by releasing the ions (e.g.,silver ions, copper ions, zinc ions, etc.). A coated bioabsorbablepolymer could also or alternatively be used as an insert inside thelumen of the device such as a cannula, cannulated screw, or as anozonated coating on a device. In another configuration the metal ionscould be coupled with a poly-anionic (negatively charged) polymer andmixed with the polymer.

For example, described herein are bioabsorbable apparatuses thatgalvanically release antimicrobial ions. The apparatus may comprise: aflexible length of bioabsorbable filament; and an ozonated coating onthe length of filament comprising an anodic metal that is co-depositedwith a cathodic metal on the length of filament; wherein the coatedfilament is flexible; further wherein the anodic metal is galvanicallyreleased as antimicrobial ions when the apparatus is inserted into asubject's body.

In general, in apparatuses (systems and devices) in which the anodicmetal and the cathodic metal are co-deposited (e.g., by vapordeposition) the anodic metal may be at least about 25 percent (e.g., atleast about 30 percent, at least about 35 percent, etc.) by volume ofthe coating. This may prevent complete encapsulation of the anodicmaterial (e.g., zinc, silver, etc.) by the cathodic material (e.g.,palladium, platinum, gold, molybdenum, titanium, iridium, osmium,niobium and rhenium). As described in greater detail below, the ozonatedcoatings applied may be configured to result in microregions ormicrodomains of anodic material in a matrix of cathodic material. Themicrodomains may be interconnected or networked, or they may be isolatedfrom each other. In general, however, the concentrations of anodicmaterial and cathodic material may be chosen (e.g., greater than 25% byvolume of the anodic material, between about 20% and about 80%, betweenabout 25% and about 75%, between about 30% and about 70%, etc.) so thatthe majority of the anodic material in the ozonated coating thickness isconnected to an outer surface of the coating, allowing eventualcorrosion of most, if not all of the anodic metal as anti-bacterialmetal ions, while providing sufficient cathodic material to provideadequate driving force for the corrosion of the anodic material. Thus,the ozonated coating may comprise the anodic metal and the cathodicmetal that have been vapor-deposited onto the length of filament so thatthe anodic metal is not encapsulated by the cathodic metal.

As mentioned, the anodic metal may comprise zinc, copper or silver, orin some variations both zinc and silver. In general, the cathodic metalhas a higher galvanic potential than the anode. For example, thecathodic metal may be one or more of: palladium, platinum, gold,molybdenum, titanium, iridium, osmium, niobium and rhenium.

As mentioned, in general the bioabsorbable substrate (e.g., filament)may comprise one or more of: polylactic acid (PLA),poly(lactic-co-glycolic acid) (PLGA), polyglycolide (PGA),polyglycoside-co-trimethylene carbonate (PGTMC),poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), andpoly(caprolactone) (PCL).

In general, the bioabsorbable substrate (including a length ofbioabsorbable filament) is configured to degrade within the body to forma degradation product, including an anion that complexes with ions ofthe anodic metal and diffuses into the subject's body to form anantimicrobial zone.

The bioabsorbable substrate (e.g., bioabsorbable filament) may beconfigured as a mesh, bag, envelope, pouch, net, or the like, that maybe configured to hold an implant. For example, the flexible structuremay be configured to at least partially house a pacemaker,defibrillator, neurostimulator, or ophthalmic implant.

Also described herein are bioabsorbable apparatuses that galvanicallyrelease antimicrobial ions and comprise: a plurality of lengths ofbioabsorbable filament arranged in a woven structure; and an ozonatedcoating on the lengths of filament comprising zinc and silver and acathodic metal that are all co-deposited onto the lengths of filament,wherein the zinc and silver are at least about 25 percent by volume ofthe coating; further wherein the zinc and silver are galvanicallyreleased as antimicrobial ions when the apparatus is inserted into asubject's body. As mentioned, the woven structure may form a mesh, bag,envelope, pouch, net, or other structure that is configured to at leastpartially enclose an implant within the subject's body.

Also described herein are bioabsorbable apparatuses that galvanicallyreleases antimicrobial ions and include: a plurality of lengths ofbioabsorbable filament; and an ozonated coating on the lengths offilament comprising an anodic metal that is co-deposited with a cathodicmetal on the lengths of filament; wherein the lengths of filament arearranged into a flexible structure; further wherein the anodic metal isgalvanically released as antimicrobial ions when the apparatus isinserted into a subject's body.

Methods of forming any of these apparatuses are also described,including methods of forming a coated bioabsorbable substrate, forexample, by co-depositing (vapor depositing) an anodic material and acathodic material onto the substrate. The substrate may be a fiber orthe structure formed of the fiber. In some variations the method mayalso include forming different regions of co-deposited anodic andcathodic materials, wherein the different regions include differentcombinations of anodic and cathodic materials. The different regions maybe non-contacting. In general, co-deposing anodic and cathodic materialsare typically performed so that the anodic material forms greater than25% by volume of the ozonated coating, preventing encapsulation of theanodic material by cathodic material within the coating.

Also described are methods of treating a subject using the bioabsorbablematerials that are co-deposited with one or more ozonated coating ofanodic and cathodic metals (e.g., materials). For example, describedherein are methods of galvanically releasing antimicrobial ions to forman antimicrobial zone around an implant that is inserted into asubject's tissue. The method may include step of: inserting into thesubject's tissue an apparatus comprising a plurality of lengths ofbioabsorbable filament having an ozonated coating comprising an anodicmetal and a cathodic metal that are co-deposited onto the lengths offilament, wherein the implant is at least partially housed within theapparatus; galvanically releasing antimicrobial ions from the coating(e.g., galvanically releasing ions of silver and zinc); allowing thelengths of filament to degrade into a degradation product includinganions, wherein the anions complex with antimicrobial ions of the anodicmetal and diffuse into the tissue to form an antimicrobial zone aroundthe implant. The method may also include inserting an implant into theapparatus before the apparatus is inserted into the subject's body. Forexample, inserting the apparatus into the body may comprise inserting aflexible apparatus comprising the plurality of length of bioabsorbablefilaments forming a bag, envelope, pouch, net or other structure (wovenor otherwise) formed to hold the implant. For example, the method mayalso include inserting a pacemaker, a defibrillator or a neurostimulatorinto the apparatus.

Inserting the apparatus may comprise inserting the apparatus having aplurality of lengths of bioabsorbable filaments coated with the anodicmetal that comprises silver and zinc that are co-deposited onto thelengths of filament with the cathodic metal.

Allowing the lengths of filament to degrade may comprise degrading thelengths of filament into anions that bind to silver ions from thecoating. For example, inserting the apparatus comprises inserting theapparatus having a plurality of lengths of bioabsorbable filamentscoated with the anodic metal that is co-deposited onto the lengths offilament with the cathodic metal, wherein the anodic metal is at leastabout 25 percent by volume of the coating (e.g., at least about 30%, atleast about 35%, etc.).

Inserting the apparatus comprising the plurality of lengths ofbioabsorbable filament may comprise inserting the apparatus having aplurality of lengths of one or more of: polylactic acid (PLA),poly(lactic-co-glycolic acid) (PLGA), and polyglycolide (PGA).

In general, the antimicrobial zone around the implant may be sustainedfor at least seven days.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIGS. 1A-1F illustrate the general concept of galvanic release of silverions.

FIG. 2A shows a cross-sectional view through one example of a substratehaving a combined coating, comprising an anodic metal that isco-deposited with a cathodic metal. These coatings (and indeed any ofthe coating and/or substrates described herein) may be ozonated, e.g.,treated with ozone to enhance the antimicrobial properties as describedherein.

FIG. 2B is a schematic representation of an enlarged view of a portionof the coated substrate of FIG. 2A, schematically illustratingmicro-domains or veins of anodic metal (not to scale) within a cathodicmatrix.

FIG. 2C is another schematic representation of an enlarged view of aportion of the coated substrate of FIG. 2A.

FIG. 2D is an example of the galvanic release (and corrosion) of acoating on a substrate such as the one shown in FIG. 2A.

FIGS. 3A-3C illustrate top views of alternative variations of coatingpatterns for different combined coatings, such as silver/platinum andzinc/platinum.

FIG. 4 is an example of a bioabsorbable pouch woven from one or morestrands, wherein the strands of the pouch are coated with the combinedcoatings described herein for release of antimicrobial ions.

FIG. 5A illustrates a fiber or filament (e.g., suture fiber) coated witha striped pattern of a combined coating for galvanic release of metalions.

FIG. 5B illustrates a portion of a barbed suture fiber coated asdescribed herein.

FIG. 5C is a portion of a suture fiber that is coated as describedherein.

FIG. 5D is an example of a needle and suture (shown as a combined needlepreloaded with suture) in which both needle and suture are coated asdescribed herein.

FIG. 6 is an example of a length of suture formed from a bioabsorbablesubstrate onto which a combined coating has been regionally applied(e.g., near the distal end).

FIG. 7 illustrates one example of a medical device configured as atransvaginal mesh having a combined coating for release of metal ionsafter insertion into the body.

FIG. 8A is a side perspective view of one example of a plug or patchthat may be used, e.g., to repair a hernia. The device is coated withmultiple types of combined coatings for galvanic release of metal ions.

FIG. 8B shows an enlarged view of one region of the plug.

FIG. 9 is a perspective view of one variation of a bandage or patchincluding a combined coating, shown on a patient's knee.

FIG. 10 illustrates one variation of an artificial dura (mesh) includinga combined coating for galvanic release of metal ions.

FIG. 11 shows an example of a material that may be used as within awound or surgical site to prevent or treat infection. The material maybe a porous and/or bioabsorbable mesh that is configured to galvanicallyrelease metal ions.

FIGS. 12A and 12B show side perspective and end views, respectively ofone variation of a cannula including a pattern of a combined coating forthe release of antimicrobial metal ions.

FIGS. 13A and 13B illustrate one example of a medical device (animplantable pacemaker) that may be used with the co-deposited galvaniccoatings described herein.

FIG. 13C is a schematic depiction of a conventional cardiac stimulationand defibrillation arrangement.

FIGS. 14A and 14B illustrate another example of a medical device (avenous catheter) that may be coated with the co-deposited galvaniccoatings described herein.

FIGS. 15A and 15B show an example of a catheter (including a cuff) thatmay include a galvanically released antimicrobial coating that isco-deposited as described herein. FIG. 15A is an example of a triplelumen device and FIG. 15B is an example of a dual lumen device.

FIG. 16 shows one example of a catheter that has been coated byco-deposition of the galvanic coating described herein.

FIG. 17A shows a cannulated bone screw that may be used with a coatedinsert as shown in FIG. 17B. The coated insert may be a bioabsorbablemesh, coated as described herein.

FIGS. 17C shows the bone screw of FIG. 17A with the mesh of FIG. 17Binserted.

FIG. 18A shows a bone screw coated as described herein.

FIG. 18B shows a bone screw similar to that shown in FIG. 18A, but whichhas been coated in a striped pattern (e.g., having regions that areeither uncoated, or coated with different anionic materials/combinationsof materials, as described in FIGS. 3A-3C, above.

FIG. 19A is another example of bone screw implant having openings orchannels from which members (shown extending in FIG. 19B) may extend.Either or both the bone screw and the extending members may be coated asdescribed herein.

FIG. 20 shows an example of an animal cage coated as described herein.

FIG. 21 shows an example of a doorknob coated as described herein.

FIG. 22A shows an example of cutlery (a fork and spoon) coated asdescribed herein.

FIG. 22B shows another example of spoon coated as described herein.

FIG. 23A show a cross-sectional view through an example of a substratesurface having a coating comprising an anodic metal co-deposited with acathodic metal, in which the coating has been cracked, enhancingavailable surface area, as described herein.

FIG. 23B is a schematic representation of an enlarged view of a portionof the coated substrate of FIG. 23A, schematically showing (not toscale) micro-domains or veins of anodic metal within a cathodic matrix,showing cracks in the coating.

FIG. 24 is a schematic outline of one method of forming an ozone coatingas described herein.

FIG. 25 is one example of piece of silver wire that were and were notozonated (e.g., treated with ozone), showing that treatment with ozoneresults in a greatly enhanced antimicrobial effect. In FIG. 25, piecesof silver wire both treated (top) and untreated (bottom) with ozone areshow in a bacterial culture dish; bacteria did not grow around thetreated wire.

FIG. 26 is an example of four galvanic silver ion releasing implants ina culture dish in which bacteria have been cultured. In this example,the two treated (ozonated, left and right) devices formed substantiallylarger ‘clearing’ regions of antibacterial activity than the unozonateddevices (top and bottom).

FIG. 27 shows an example of a mesh coated with co-deposited silver and acathodic metal as discussed herein, in which the left-hand side coatedmeshes where treated with ozone, resulting in substantially largeclearing regions where antimicrobial activity prevented bacterialgrowth, and the right-hand side including a mesh that was uncoated anduntreated with ozone, showing bacterial growth.

FIGS. 28A and 28B illustrate alternative variations of microbialcultures in the presence of treated (ozonated) mesh materials includinga coating of a co-deposited sliver and cathodic metal as describedherein.

DETAILED DESCRIPTION

In general, described herein are apparatuses (e.g., systems and devices)that include a an anionic metal material (e.g., silver) that has beentreated with ozone to enhance the antimicrobial properties of theanionic metal. For example, described herein are ozonated coatings orlayers that galvanically releases antimicrobial ions over an extendedperiod of time. The coating may be applied to a substrate, e.g., abioabsorbable and/or biodegradable substrate that may degrade during thesame period that the antimicrobial ions are being released, e.g., days,months, years. In some variations the substrate may be coated with anadhesion layer on the substrate. The substrate may be pre-treated (e.g.,to remove oxides, such as the titanium oxide layer on a nickel titaniumsubstrate). In general, the coating may include a combination of anodicmetal (and particularly silver alone or in combination with one or moreof zinc and/or copper), and a cathodic metal, such as palladium,platinum, gold, molybdenum, titanium, iridium, osmium, niobium andrhenium, where the anodic metal and cathodic metals are co-deposited(e.g., by vapor deposition) so that the anodic metal is exposed to anouter surface of the coating and not fully encapsulated in the cathodicmetal, and there is sufficient cathodic metal to drive the galvanicrelease of anodic ions when exposed to bodily fluids such as blood,lymph, etc. (e.g., when implanted into the body). Finally, the coatingmay be treated with ozone to supercharge the antimicrobial effectspresent in normal galvanically released silver ions.

For example, described herein are apparatuses including substrates ontowhich anodic metal and cathodic metals are co-deposited to form acoating that is ozonated, allowing the anodic metal to be galvanicallyreleased as ions (e.g., antimicrobial silver, copper and/or zinc ions)when the apparatus is exposed to a conductive fluid (e.g., a bodilyfluid). The substrate may include an adhesive coating (such as atantalum or titanium layer that is applied before the galvanic coatingof co-deposited antic and cathodic metal).

Galvanically Releasable Coating

In general, the antimicrobial metal ion coatings described herein aregalvanically releasable within a tissue, and include one or more anodicmetal (typically silver and/or zinc and/or copper) that is co-depositedwith a cathodic metal (typically platinum and/or palladium). Any of thecoatings mentioned herein may be ozonated as described below. The anodicmetal and the cathodic metal are co-deposited, e.g., by sputtering orother appropriate methods described herein, so that the resultingcoating is non-homogenous, with a percentage of anodic metal (e.g.,silver) that is greater than about 30% co-distributed (typically inclusters, veins or clumps as illustrated and described below) with thecathodic metal (e.g., platinum), where the cathodic metal is greaterthan about 30% (e.g. w/w) of the coating. The antimicrobial metal ioncoatings described herein may be generally referred to as non-homogenousmixtures where the anode is distributed in connected clusters (veins)within the cathodic metal (or vice-versa). Generally, both the anodicmetal and the cathodic metal are exposed in microdomains across theouter surface of the coatings, allowing galvanic release; as the anodicmetal is released, it may form channels (e.g., tunnels, mines, etc.)through the coating, e.g., within the cathodic material. In somevariations the cathodic material remains behind. In some variations someof the cathodic material may also be released.

Thus, in any of these variations, the coating may comprise a non-uniformmixture of the anodic and cathodic metals, with a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal, and/or a plurality of microregions or microdomains of cathodicmetal in a matrix of anodic metal. These microregions or microdomainsmay be formed by co-deposition as described herein.

Any of the coatings described herein may include co-deposited multipleanodic and/or multiple cathodic metals forming the coating. In somevariations, it may be preferable to separate regions having a firstanodic metal (e.g., silver) from regions having a second anodic metal(e.g., zinc), so that they are separated (e.g., in some variationselectrically separated) and/or non-contacting, allowing preferentialrelease of one metal ion (e.g., zinc) compared to silver. This may allowcontrol of the release profile, and may extend the length of effectiverelease time for as coating.

In general, these coatings may be any appropriate thickness. Forexample, the thickness could be a few microns thick or more (e.g.,greater than 2 microns, greater than 5 microns, greater than 10 microns,greater than 15 microns), etc. For example, the thickness of the coatingmay be between about 10 microinches (approximately 2500 Angstroms orapproximately 0.25 microns) and about 25 microinches (approximately 6350Angstroms or about 0.64 microns). The thickness of the coating may beuniform or non-uniform. Only some regions of the substrate may becoated, while other regions may be masked to prevent coating. Forexample, in an electrical stimulation apparatus (e.g., cardiacstimulator, neurostimulator, etc.) the body and/or connectors of thedevice may be insulated while the electrical leads (electrical contacts)to deliver energy to the tissue may be uncoated. Alternatively in somevariations the electrical contacts are coated as described herein.

FIGS. 1A-1F conceptually describe a simple galvanic cell setup such asfor use in a body. The setup is shown treating an infection, but thesame process could be applied to healthy tissue to prevent an infection(prophylactically). The components including a first metal 2 (e.g.,silver), second metal 4 (e.g., platinum), and electrolytic fluid 6(e.g., blood) are shown individually in FIGS. 1A-1C and arranged in atissue in FIGS. 1D-1F. Electrolytic body fluid 6 is shown bathing orcontacting healthy tissue 10 as well as infected tissue 8. When silvermetal 2 contacts platinum metal 4 in body fluid 6, it forms a galvaniccell with a silver anode and platinum cathode. As shown in FIG. 1E,ionic silver 12 is generated and spreads through the body fluid, killingmicroorganisms and creating an infection-free zone 14 in body fluid 16in the vicinity of the anode. After treatment is complete, the silveranode 2 may be completely corroded 20 leaving an infection-free bodyfluid 18. Any metal with a higher redox potential than silver may beused as the cathode. The metal may be a noble metal, such as gold,palladium or platinum. Although the example shown in FIGS. 1A-1Fdescribes using a silver metal anode that is placed adjacent to aplatinum metal cathode, described herein are coatings in which theanodic metal (e.g., silver, zinc, copper) is co-deposited onto abiodegradable substrate.

In general, a coating of anodic metal and cathodic metal may beconfigured so that the anodic metal and cathodic metal are within thesame coating layer. The microregions of anodic metal may be embeddedwithin the cathodic metal, including being embedded within a matrix ofcathodic metal (or vice versa). As illustrated below, the microdomainsor microregions of anodic metal are within a cathodic matrix, allowing alarge spatial release pattern of anodic metal ions by galvanic actiontriggered by the contact of the anodic metal and the cathodic metalwithin the electrolytic bodily fluid. The coatings described herein, inwhich the anodic metal and the cathodic metal are combined as part ofthe same layer may be referred to as “combined” coatings, in which ananionic metal and a cationic metal are both jointly coated, and/ornon-homogenous (non-uniform) mixtures of anodic and cathodic metal.

The combined coatings described herein may be non-uniform mixtures ofanodic and cathodic metals. For example, the anionic metal may formmicroregions or microdomains within the cationic metal (or vice versa).In general, the cathodic metal microdomains may form one or more(typically a plurality) of continuous paths through the cathodic metal.For example, the microdomains described herein may be veins, clusters,threads, clumps, particles, etc. (including interconnected veins,clusters, threads, clumps, particles, etc.) of anodic metal, e.g.,silver, copper, and/or zinc, etc., that are connected to an outersurface of the coating, so that they are exposed to the electrolyticbodily fluid (e.g., blood). The microdomains of anodic metal may form anetwork within the matrix of the cathodic metal. Thus, the anodic metalsmay be present in one or more networks that are electrically connectedwithin the cathodic matrix. The individual sizes of particles, threads,branches, veins, etc. forming the microdomains may be small (typicallyhaving a length and/or diameter, e.g., less than a 1 mm, less than 0.1mm, less than 0.05, less than 0.01 mm, less than 0.001 mm, less than0.0001 mm, less than 0.00001 mm, etc.). Similarly, in some variationsthe matrix may be the anodic metal and the cathodic metal may bereferred to as forming microdomains (e.g., where the percentage ofcathodic metal in the coating is less than 50%, less than 45%, less than40%, less than 30%, etc. by volume of the coating).

A combined anodic metal and cathodic metal forming a combined coating(or a portion of a coating) may be formed of a single anodic metal(e.g., silver) with a single cathodic metal (e.g., platinum), which maybe referred to by the combined anodic metal and cathodic metals formingthe coating or portion of a coating (e.g., as a combined silver/platinumcoating, a combined silver/palladium coating, a combined zinc/platinumcoating, a combined zinc/palladium coating, etc.). In some variations acombined coating may include multiple anodic and/or cathodic metals. Forexample, the combined coating may include zinc and silver co-depositedwith platinum.

As mentioned, the anodic metal in the combined coating may include acontinuous path connecting the anodic metal to an exposed outer surfaceof the coating so that they can be galvanically released from thecoating. Deeper regions (veins, clusters, etc.) of the anodic metal maybe connected to more superficial regions so that as the more superficialregions are corroded away by the release of the anodic ions, the deeperregions are exposed, allowing further release. This may also exposeadditional cathodic metal. Thus, in general, anodic metal microdomainsare not completely encapsulated within the catholic metal. In somevariations, the majority of the anodic metal is not completelyencapsulated within the cathodic metal, but is connected to an exposedsite on the surface of the coating via connection through a moresuperficial region of anodic metal; although some of the anodic metalmay be completely encapsulated. For example, the coating may include ananodic metal in which less than 50 percent of the total anodic metal iscompletely encapsulated within the cathodic metal (e.g., less than 40%,less than 35%, less than 30%, less than 25%, less than 20%, less than15%, less than 10%, etc.).

The co-deposited anodic and cathodic combined coatings described hereinfor the galvanic release of anodic ions may be formed by co-depositingthe anodic metal and the cathodic metal so as to minimize the amount ofencapsulation by the cathodic material. For example, the percentage ofthe anodic material may be chosen so that there is both an optimalamount of cathodic metal to drive reasonable galvanic release in thepresence of an electrolyte, and so that there is sufficient continuityof anodic metal with the combined coating to form a continuous path toan exposed surface of the coating, making it available for galvanicrelease. For example, a coating may be formed by co-depositing theanodic metal and the cathodic metal (e.g., sputtering, vapor deposition,electroplating, etc.) where the concentration of the anodic metal ishigh enough to allow the formation of a sufficient number of continuouspaths through the thickness of the coating. We have found that acombined coating in which more than 25% by volume (or more preferablymore than 30%) of the coating is formed of the anodic metal issufficient to form a combined coating with a cathodic metal in whichmore than half (e.g., >50%) of the anodic metal is connected by acontinuous path to the surface of the coating, permitting galvanicrelease. For example, a coating having between about 33-67% of anodicmetal and between about 67-33% of cathodic metal may be preferred. Atthese percentages, less than half of the anodic metal is fullyencapsulated by the non-corroding cathodic metal and trapped within thecoating. Thus, in general, the combined coatings (also referred to asco-deposited coatings) may include more than 25% (e.g., 30% or greater,35% or greater) by volume of anodic metal that is co-deposited with thecathodic metal. In some variations, the remainder of the coating (e.g.,between 5% and 75%,) may be cathodic metal. Thus, the percent of anodicmetal co-deposited with cathodic metal may be between 25%-95% (e.g.,between about 30% and about 95%, between about 30% and about 90%,between about 30% and about 80%, between about 30% and about 70%,between about 25% and 75%, between about 25% and 80%, between about 25%and 85%, between about 25% and 90%, between about 35% and 95%, betweenabout 35% and 90%, between about 35% and 85%, between about 35% and 80%,between about 35% and 75%, between about 35% and 70%, between about 35%and 65%, etc.), with the remainder of the coating being cathodic metal.Further, the coating (or at least the outer layer of the coating) may beprimarily (e.g., >95%) formed of anodic and cathodic metals distributedin the micro-domains as described herein. In some variations the coatingmay also include one or more additional materials (e.g., a metal,polymer, or the like). The additional material(s) may be inert (e.g.,not participating in the galvanic reaction between the anodic metal andthe cathodic metal), or it may be electrically conductive. For example,the additional material may be co-deposited with the anodic and cathodicmetals, and may also be distributed in a non-homogenous manner.

For example, a mixed coating may be formed using a PVD-system.Vaporization of metal components may be performed on a substrate (withor without an adhesive layer), e.g., using an arc and/or a magnetronsputter from metallic targets. Mixed coatings may be produced bysimultaneous vaporization of both metals while the substrate is heldfixed, or is moved (e.g., rotated). After coating, the coated materialsmay be cleaned, e.g., using an argon plasma and/or other methods.

As mentioned, any of the coatings described herein may be of anyappropriate thickness. For example, the coatings may be between about500 microinches and about 0.01 microinches thick, or less than about 200microinches (e.g., between about 10 microinches and about 500microinches), less than about 150 microinches, less than about 100microinches, less than about 50 microinches, etc. The thickness may beselected based on the amount and duration (and/or timing) of the releaseof anodic metal. In addition, the coatings may be patterned, e.g., sothat they are applied onto a substrate in a desired pattern, or over theentire substrate. As mentioned and described further below, differentcombined coatings may be applied to the same substrate. For example, acombined coating of silver/platinum may be applied adjacent to acombined coating of zinc/platinum, etc. The different combined coatingsmay have different properties (e.g., different anodic metal, differentanodic/cathodic metal percentages, different thicknesses, etc.) andtherefore different release profiles. Combinations in which differentcombined coatings are in (electrical) contact with each other may alsohave a different release profile than combinations in which thedifferent coatings are not in electrical contact. For example, amaterial may include a first combined coating of zinc and a cathodicmetal (e.g., zinc/platinum) and a second combined coating of silver anda cathodic metal (e.g., silver/platinum). If the first and secondcombined coatings are in electrical contact, the zinc will begalvanically released first. If the first and second combined coatingsare not in electrical contact, then both zinc and silver will beconcurrently released (though zinc may be released more quickly and mydiffuse further).

For example, FIG. 2A illustrates one example of a substrate 120 ontowhich a combined coating of anodic and cathodic metals have beenco-deposited 100. The substrate may be, for example, a bioabsorbablematerial. In some variations the substrate may be an adhesive layer,e.g., when applying the coating to some medical devices. For example, anadhesive layer may be a metal layer such as an undercoating of titaniumor tantalum. The undercoating may be of any appropriate thickness (e.g.,the same thickness or smaller than the thickness of the galvanicallyreleasing coating). In some variations the undercoating is thicker thanthe coating of the non-homogeneous mixture of anodic and cathodic metalsthat are galvanically released. Although an undercoating may be used insome variations, the coatings of anodic and cathodic metals describedherein may be coated directly onto a medical device (e.g., implant)without the need for an undercoating.

Although the combined coatings described herein may be used with anysubstrate (even non-bioabsorbable substrates), any of the examplesdescribed herein may be used with bioabsorbable substrates. In theexample of FIG. 2A the dimensions (thicknesses of the substrate andcoating) are not to scale. For example, the coating may be less than 100microinches thick. The substrate may be any thickness. In FIG. 2A,region B shows a portion of the coating and substrate, which isillustrated in the enlarged view of FIG. 2B.

In FIG. 2B, a portion of the substrate 120 (e.g. a bioabsorbablesubstrate) is shown coated with a combined coating 100. The anodicmetal, e.g., silver, 110 is shown forming veins or microregions withinthe cathodic metal 130. In this example, the silver is schematicallyillustrated as forming veins through a matrix of cathodic metal, e.g.,platinum, not shown to scale. The actual microdomains may be muchsmaller, and filamentous; for example, the microdomains may be on theorder of 10-1000 Angstroms (or more) across. FIG. 2C is anotherschematic illustration of a section through a portion of a combinedcoating on a substrate, showing microdomains of anodic metal (e.g.silver) 110, within a matrix of cathodic metal (e.g., platinum) 130. InFIGS. 2B and 2C the majority of the microdomains of anodic metal areconnected in continuous paths to the outer surface of the coating 100,allowing galvanic release of the anodic material.

FIG. 2D illustrates an example of the coating of FIG. 2C during thegalvanic release process, in which the implant including the substrateand the combined coating is place into the body, so that the coating isexposed to blood. As shown in FIG. 2D, the anodic metal (silver) in thecoating is progressively corroded as ions of silver are released intothe body to locally diffuse and provide regional antimicrobialtreatment. In this example the anodic metal (e.g., silver) 120 exposedto the surface is release, leaving a negative impression in the cathodicmetal 130. Regions of the cathodic metal that are left behind may remaincoated (though the substrate may also be biodegrading simultaneous withthe release of anodic metal, not shown). Typically, when the substrateis part of an implanted apparatus, the coating layer is thin enough thatany remaining cathodic metal (e.g., platinum) is small enough to beignored or easily cleared by the body.

The combined layers are generally formed by co-depositing the anodicmetal and the cathodic metal onto the substrate. For example, a combinedlayer may be formed by simultaneously sputtering the two metals onto thesubstrate to the desired thickness. For example, both silver andplatinum may be placed into a sputtering machine and applied to thesubstrate. The amount of cathodic material and anodic material may becontrolled, e.g., controlling the percentage of the coating that ifanodic metal and the percentage that is cathodic (e.g., 30%-70%anodic/70-30% cathodic, such as 40% silver/60% platinum, etc.). Thissputtering process results in a non-uniform pattern, as discussed above,and schematically illustrated in FIGS. 2B-2C, which may be observed.Alternatively, combined layers may be formed by vacuum deposition, orany other technique that can co-deposit the two (or more) metals ontothe substrate. Formation of the coating(s) may include masking, forexample, locating coatings in particular regions of the substrate.

In general, any of the substrates (e.g., bioabsorbable substrates)described herein may be applied in a pattern, including patterns ofmultiple different combined coatings. Further, coatings may be appliedover only apportion of the substrate, which may allow more localizedrelease of the antimicrobial ions and may prevent the coating frominterfering with the properties of the substrate and/or the device thatthe substrate is part of (e.g., flexibility, surface characteristics,etc.). For example, FIGS. 3A-3C show a top view of a substrate coatedwith various combined coatings (co-deposited anodic and cathodicmetals).

For example, in FIG. 3A, the surface of the substrate 210 of an implant200 that includes alternating patterns of a first combined coating 212of silver/platinum that have been co-deposited onto the substrate and asecond combined coating 214 of zinc/platinum co-deposited onto thesubstrate. In this example the first and second coating regions areformed into strips extending along the width of the substrate; the firstand second coating regions do not overlap and are not in electricalcontact with each other. Thus, the silver ions in the first coatingregion(s) 212 will be galvanically released concurrently with the zincions galvanically released from the second coating region(s) 214 whenexposed to an electrolytic bodily fluid (e.g., blood), corroding the twolayers. FIG. 3B shows another example of a pattern of a first combinedcoating 212 (e.g., silver/platinum) and a second combined coating 214(zinc/palladium) that are arranged with alternating stripes on thesurface of the substrate 210, where the stripes are end-to-end with eachother.

FIG. 3C shows another variation of a surface 210 of an implant 200 thatincludes a pattern, shown as a checkerboard pattern, of first and secondcombined coatings. In FIG. 3C, the edges of the different coatingregions may contact each other or may be separated by a channel so thatthey are not in electrical contact for the galvanic reaction. Forexample, if the first and second regions do contact each other so thatthey are in electrical contact, then the galvanic reaction may drive therelease of the zinc ions before the release of the silver ions; once thezinc has corroded, the silver ions may be released.

In general, there may be some benefit to including multiple coatings,and in particular coatings having multiple anodic metals. Theantimicrobial region around the coated implant may be made larger andthe ions may be released over a longer time period, than with a singletype of anodic coating alone.

As mentioned, the combined coatings of co-deposited anodic and cathodicmetals could be formed in any pattern. As mentioned above, all or aportion of these coatings/surfaces may be ozonated by treatment withozone to enhance the effects seen.

Bioabsorbable Substrates

In some variations, the substrate is bioabsorbable and/or biodegradable.For example, the substrate may be formed as a flexible filament, and thecoating of anodic and cathodic metals that may corrode to release anodicions may allow the flexible filament to remain flexible. Galvanicrelease results in degradation (e.g., corrosion) of the coating.

The substrate onto which the combined coatings may be applied may be anyappropriate substrate, and in particular, may be a bioabsorbablesubstrate. Examples of bioabsorbable materials that may be used includespolymeric materials such as: polylactic acid (PLA),poly(lactic-co-glycolic acid) (PLGA), polyglycolide (PGA),polyglycoside-co-trimethylene carbonate (PGTMC),poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), andpoly(caprolactone) (PCL), and combinations of these.

In general, bioabsorbable materials for medical applications are wellknown, and include bioabsorbable polymers made from a variety ofbioabsorbable resins; for example, U.S. Pat. No. 5,423,859 to Koyfman etal., lists exemplary bioabsorbable or biodegradable resins from whichbioabsorbable materials for medical devices may be made. Bioabsorbablematerials extend to synthetic bioabsorbable or naturally derivedpolymers.

For example, bioabsorbable substrates may include polyester orpolylactone selected from the group comprising polymers of polyglycolicacid, glycolide, lactic acid, lactide, dioxanone, trimethylenecarbonate, polyanhydrides, polyesteramides, polyortheoesters,polyphosphazenes, and copolymers of these and related polymers ormonomers. Other bioabsorbable substrates may include substrates formedof proteins (e.g., selected from the group comprising albumin, fibrin,collagen, or elastin), as well as polysaccharides (e.g., selected fromthe group comprising chitosan, alginates, or hyaluronic acid), andbiosynthetic polymers, such as 3-hydroxybutyrate polymers.

The bioabsorbable substrate may be absorbed over a predetermined timeperiod after insertion into a body. For example, the bioabsorbablesubstrate may be absorbed over hours, days, weeks, months, or years. Thesubstrate may be bioabsorbed before, during or after release of theanodic metal ions from the combined coating. In some variations therelease of the antimicrobial ions is timed to match thedegradation/absorption of the substrate. Further, the absorption of thesubstrate may facilitate the release of the anodic metal ions. Forexample, some of the bioabsorbable substrates described herein mayresult in a local pH change as the substrate is bioabsorbed; the releaseof the metal ions may be facilitated by the altered pH.

FIG. 4 shows an example of a pouch device formed from woven lengths ofbioabsorbable filament that is flexible. The filament is formed of abioabsorbable polymer, PGLA, and this bioabsorbable substrate has beencoated with the combined anodic metal/cathodic metal coating describedabove. In FIG. 4A, the pouch of PGLA fibers coated with (e.g., by vapordeposition) co-deposited silver and platinum galvanically releasessilver ions after insertion into the body. The release of anodic metalions (e.g., silver ions) is enhanced as the bioabsorbable substrate(e.g., PGLA) is hydrolyzed. Hydrolysis lowers the local pH and this mayincrease solubility of silver and bio-absorption.

The pouch of FIG. 4 may be used similarly to those described in U.S.Pat. No. 8,591,531, herein incorporated by reference in its entirety.

In general, the bioabsorbable substrate may be formed into anyappropriate shape or structure. For example, a bioabsorbable substratemay be a filament that is coated, completely or partially, by one ormore of any of the combined coatings of anodic and cathodic metalsco-deposited onto the bioabsorbable substrate. Coated strands (e.g.,filaments, strings, wires, etc.) of bioabsorbable substrate may be usedby themselves, e.g., as suture, ties, etc. within a body, or they may beused to form 2D or 3D implants, for example, by weaving them. Thecombined coatings described herein may be coated onto these structureseither before or after they have been formed. For example, a coatedfilament may be woven into a net (or into a pouch for holding animplantable device, as shown in FIG. 4), or the filament may be woveninto a net and then coated.

FIG. 5A shows an example of a filament that may be formed of abioabsorbable substrate that is coated with a combined anodic/cathodicmetal coating for galvanic release of anodic metal ions. In FIG. 5A, thefiber 500 may include uncoated regions 505 alternating with coatedregions 503. The coated region(s) may be a spiral shape around thefiber, a ring around the fiber (as shown in FIG. 5) or any otherpattern. Multiple coatings may be used (see, e.g., FIGS. 3A-3C). Thecoated fiber may retain its flexibility. In some variations the fibermay be used, e.g., as a suture.

FIGS. 5B-5D and 6 illustrate different variations of sutures that may becoated as described herein. Note that although some of these substratesforming the suture are bioabsorbable, they do not need to be. In somevariations, the suture material (the substrate onto which thegalvanically releasable coating is applied) is not biodegradable orbioabsorbable. Any variation of suture material may be used. Forexample, the suture material may be a barbed suture, as shown in FIG.5B. The barbed suture 560 may be coated 565 or otherwise treated toinclude the co-deposited coating of anodic metal (e.g., 40% by volume ofsilver) and cathodic metal (e.g., 50% by volume of platinum) arrangedwith continuous microdomains of the anodic (and/or cathodic) metalextending from the outer side of the outer surface of the coatingthrough the thickness of the coating. An entire length of suture 580 maybe coated 585, as shown schematically in FIG. 5C, or just a portion ofthe suture. The thickness of the coating may be below a threshold, whichmay help maintain the flexibility of the suture material. For example,the thickness may be between 10 microinches and 50 microinches. FIG. 5Dillustrates a suture kit including a length of suture 580 and a needle591; either or both the suture 580 and needle 591 may be coated. Thesame or different anodic metal and/or cathodic metal may be used on theneedle as the thread. For example, the needle may include the morequickly releasing nickel as the anode, while the thread, which resideslonger in the body, may use and anodic metal of silver.

FIG. 6 shows another example of a suture 600 that is coated 620 over thedistal portion of the suture, which may be used in the body. The suturemay be pre-loaded on a device (including an implant, needle, etc.). Thesuture may be formed of a bioabsorbable substrate 610 onto which thecoating is applied.

In any of the devices described herein, the coating may be made directlyonto the substrate. In some variations the coating may be made on top ofanother coating (e.g., a primer coating) which may be made to preparethe substrate for the coating. Examples of primer coatings are adhesioncoatings. An example of a primer coating may include titanium and/ortantalum undercoatings, as described above.

Additional examples of woven structures are shown in FIGS. 7-11. In FIG.7, the device 700 is formed of filaments 710 woven or arranged into amesh (shown in the enlarged view 720) that are coated with a combinedcoating (or multiple types of combined coatings) as described herein. Inthis example, the mesh formed is configured as a transvaginal mesh(intravaginal mesh) that may be used for the treatment of vaginalprolapse, for example. Slings or other anatomical support structures,either durable or biodegradable, could also be formed. These devices maygalvanically release one or more type of anionic metal ion havingantimicrobial effect. For example the mesh may be coated with a coatingof silver/platinum that is co-deposited onto the mesh or the fibersforming the mesh for galvanic release of silver from the coating.

FIGS. 8A and 8B illustrate another example of a structure, shown as awoven structure, that may also be configured as a non-woven (e.g.,solid) structure. In FIG. 8A the device 400 is a patch or plug that maybe used for treating a hernia. In this example, the patch is a wovenmesh that includes two types of combined coatings: silver/platinum andzinc/platinum in different regions over the surface of the patch. Darkerregions 803 may indicate the silver/platinum co-deposited coatingregions, while the lighter regions 805 represent co-depositedzinc/platinum regions. The entire patch outer surface or only a portionof the outer surface may be coated; in FIG. 8A, only discrete regionsare shown as coated, for the sake of simplicity. FIG. 8B shows anenlarged view illustrating the fibers forming the weave of the patch. Asshown in FIG. 8B, only some of the fibers are coated (e.g., every otherfiber of the warp); in some variations, alternating fibers in onedirection (warp) are coated with different anodic/cathodic metals, whilefibers in the opposite direction (weft) are uncoated.

FIG. 9 illustrates another example of a woven material, formed of abioabsorbable fiber, coated with the combined coatings described hereinfor galvanic release of antimicrobial metal ions. In FIG. 9, the deviceis a patch that could be used, e.g., within the knee after surgery, toreduce the chance of infection. In this example, as in FIGS. 8A and 8Babove, the patch may include filaments/fibers having different coatings(e.g., silver/platinum, zinc platinum, silver palladium, zinc palladium,etc.) and/or different regions on the patch, as shown by the light anddarker regions in FIG. 9. In some variations the patch may be wornoutside of the body, e.g., it is “implanted” by placing it over a wound,rather than entirely within the body. Blood in the wound region may actas the electrolytic fluid, allowing galvanic release of the metal ions.

Similarly, FIG. 10 illustrates a dural replacement mesh 810 that may beimplanted into a subject's head 812 to replace dural matter followingtrauma and/or surgery. The mesh may be formed of a non-bioabsorbablematerial (or a bioabsorbable material) that is coated as described aboveso as to galvanically release antimicrobial metal ions.

FIG. 11 illustrates another example of a fabric or mesh that may beimplanted into a patient as part of a surgical procedure. In FIG. 11,the mesh is a woven fabric that has been coated with one or morecombined coatings of anodic and cathodic metals co-deposited on thesubstrate (e.g., bioabsorbable substrate) for galvanic release of metalions. The material may be used, for example, as part of a large jointprocedure such as knee replacement, or spinal surgery (e.g., fixationusing rods, screws, etc.) in place of currently used antibiotic powers.For example the coated bioabsorbable mesh could be in, around, or overthe surgical site and used to galvanically release antimicrobial ionsfollowing surgery. The implant (material) would break down over time,and be absorbed following implantation (e.g., within 30 days followingthe procedure), allowing sufficient time for the patient to recover andavoid infection potentially introduced by the procedure and/or theresulting wound.

Although the devices described herein include flexible, e.g., filamentor mesh, structures, the devices may also be configured as rigid or moretraditional surgical implants, including screws, rods, staples,cannulas, etc. The substrate may be bioabsorbable.

For example, FIGS. 12A-12B shows one variation of a cannula that may beused within a body and galvanically release antimicrobial metal ions. InFIG. 12A, the cannula 300 includes a substrate 320 onto which a combinedcoating 330 is applied in a spiral pattern. The combined coatinggalvanically releases anodic metal ions (e.g., silver, zinc, copper), isincludes the anodic metal that has been co-deposited with cathodic metal(e.g., platinum, palladium, etc.). In this example, the inner surface310 of the cannula 300 may also be separately coated with a combinedcoating (the same or a different coating). FIG. 12B shows a side view ofthe catheter of FIG. 12A.

Any of the devices described herein may be used as part of a surgicalprocedure within a body (e.g., human, animal, etc.). In general, thecombined coatings described herein may be implanted into the body andmay galvanically release metal ions over an extended period of time(e.g., days, weeks, months). For example, in some variations the coatingand/or apparatus (e.g., device) may be configured to galvanicallyrelease metal ions for 30 days, 60 days, 90 days, or more.

The anti-microbial coatings, devices and systems described herein mayuse two or more types of metal ions with anti-microbial properties, suchas silver and zinc. The zone of inhibition of microbial activity/growthformed around the coated devices due to the released metal ions may beenhanced where two different types (e.g., silver and zinc) are released.The combination of zinc and silver has been observed to have asynergistic effect compared to either metal alone.

Further, when the combined coatings described herein are used incombination with a bioabsorbable (e.g., biodegradable) substrates ormaterial, the metal ions may form complexes with the byproducts ofdegradation of the substrate (e.g., polymeric substrates including PLA,PLGA, PGA) such as lactate, galactate, or glucoate. These substrates mayincrease the anti-microbial activity. For example, the range ofdiffusion of the anionic metal ions (e.g., zinc, silver, etc.) may beincreased by the creation of a complex between the metal ions and thepolymeric degradation byproduct. Further, as mentioned above,degradation of the polymers may create acidic byproducts such as lacticacid, galactic acid, and/or glycolic acid. The drop in pH and formationof the anionic byproducts may further enhance the rate of the galvanicreaction.

Thus, the apparatuses and methods above may, in some variations,generally take advantage of the use of bioabsorbable substrates that arecoated through a co-deposition process of a cathodic metal (e.g.,platinum, palladium, gold, etc.) and an anodic metal (e.g., silver,zinc, copper) to form a galvanic circuit in a fluid (e.g., electrolytic)medium to create an antimicrobial zone. The degradation of thebioabsorbable substrate may further enhance this antimicrobial zone,e.g., by forming complexes with the released metal ions to furtherdiffuse the ions as well as to alter the local pH to enhance thegalvanic reaction. In general, as described above, the combined coatingsdescribed herein can be quite thin and do not compromise theflexibility, chemic structure, strength (e.g., tensile strength) orchemical properties of the underlying substrate(s).

EXAMPLES

Any of the coatings described herein may be ozonated and may be includedon all or a portion of a medical device. For example, any of thefollowing devices may be wholly or partially coated with a mixture of ananodic metal and a cathodic metal as described herein: shunts (e.g.,drainage shunts, dialysis shunts, etc.), catheters (e.g., urinarycatheters, intravascular catheters, etc.), ports (e.g., portacath,etc.), artificial joints (e.g., total hip, knee, etc.), pacemakers,defibrillators (ICD), pain management implants, neuro-stimulators,neuro-pacemakers, stents, bariatric balloons, artificial heart valves,orthodontic braces, pumps (drug pumps, e.g., insulin pumps, etc.),implantable birth control devices, IUDs, etc.

Any of the coatings described herein may be included on all or a portionof a medical tool. For example, any of the following materials for usein operating on a subject may be wholly or partially coated with amixture of an anodic metal and a cathodic metal as described herein:surgical gauze, surgical sponges, wound packing materials, augmentationand/or cosmetic implants (e.g., breast/chin/facial implants), surgicalretractors, needles, clamps, forceps, and the like.

For example, FIG. 13B illustrates one example of an implant that may becoated on an outer surface with any of the antimicrobial coatingscomprising a non-homogeneous mixture of anodic and cathodic metals forgalvanic release of anti-microbial ions, as described herein, andimplant as illustrated in FIG. 13A. In this example all or just aportion of a pacemaker 1301 may be coated on an outer surface with themixture of between about 30% and 70% by volume of an anodic metal, andbetween about 30% to 70% by volume of a cathodic metal. The anodic andcathodic metals may be co-deposited on the outer substrate surface toform a non-uniform mixture of the anodic and cathodic metals, whereinthe coating comprises a plurality of microregions or microdomains ofanodic metal in a matrix of cathodic metal or a plurality ofmicroregions or microdomains of cathodic metal in a matrix of anodicmetal. In some variations different regions may be coated with differentanodic metals (e.g., forming a pattern of silver, nickel, etc. releasingregions). In some variations the electrical leads (e.g., an outersurface of the leads that are tunneled through the body, as illustratedin FIG. 13A) may be coated as described herein. Similarly, electricalleads for other devices (e.g., neurostimulators) may be coated asdescribed herein. In general, these coatings may terminate before theelectrically active regions of the lead.

For example, FIG. 13C shows a schematic depiction of an implantablepacemaker (defibrillator) system 1300 including electrodes implanted inthe heart H of a subject (patient). A cardiac stimulation anddefibrillation device 1310 is connected to the heart H via an electrodelead 1320 which comprises three lead branches or electrode supply leads1330, 1340 and 1350. Each lead branch comprises sensing or stimulationelectrodes (which are not depicted individually) on or near the distalend thereof, and lead branch 1350 also comprises an elongateddefibrillation electrode 1360. In the arrangement shown, lead branch1330 is placed in the right atrium, lead branch 1340 is placed in theleft atrium of the heart H, and lead branch 1350 on which defibrillationelectrode 1360 is installed is placed in the right ventricle (RV). Asmentioned above, any of the leads described herein may be coated withthe mixture of between about 25% to 75% (e.g., 30% and 70%) by volume ofan anodic metal, and a cathodic metal that are co-deposited on the outersubstrate surface to form a non-uniform mixture of the anodic andcathodic metals. The coatings may include the electrical contacts (notshown) or the contacts may not be coated. Different coatings may be used(e.g., different anodic and/or cathodic metals, different patterns ofcoating, etc.) may be used. In general, the coating comprises aplurality of microregions or microdomains of anodic metal in a matrix ofcathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of anodic metal. This coating may be made onthe leads without detrimentally affecting the flexibility of the leads.For example, the coating may be applied thin enough to allow the lead tobend easily, while still providing sufficient elution of antimicrobialmetal ions (e.g., silver ions) over a long time period (of weeks andmonths).

FIGS. 14A and 14B, as well as FIGS. 15A and 15B illustrate anothervariation of a type of device, a catheter such as a Venus catheter thatmay be partially or completely coated as described herein. The coatingsdescribed herein may benefit virtually any type of catheter; a Venuscatheter is generally a tube inserted into a vein in the neck (as shownin FIG. 14A), chest, or leg, e.g., near the groin, usually only forshort-term hemodialysis. In FIG. 14A, the tube splits in two after thetube exits the body. The two tubes have caps designed to connect to theline that carries blood to the dialyzer and the line that carries bloodfrom the dialyzer back to the body. A person must close the clamps oneach line when connecting and disconnecting the catheter from the tubes.Any portion (or the entire device) may be coated as described herein.For example, in FIGS. 14A and 14B, the outer surface of the catheter1405 and/or the Venus and arterial lines may be coated as describedherein.

In some devices, it may be helpful to provide a cuff or cuffs on thedevice that are specifically configured for the galvanic release ofantimicrobial ions. For example, FIGS. 15A and 15B illustrate catheters1500, 1501 for long-term vascular access that includes a cuff that maybe at least partially coated as described herein for the release ofantimicrobial ions. Adjacent to the ion-releasing cuff 1505 is atissue-ingrowth cuff 1507.

In general, the wide use of invasive medical devices, includingintravascular catheters has led to an increase in infections related tothe use of the medical device. However, intravascular catheters areoften associated with serious infectious complications, such ascatheter-related bloodstream infection (CRBSI). In fact, CRBSI isconsidered to be the most common type of nosocomial bloodstreaminfection, a finding that has been attributed to the wide use ofintravascular catheters in hospitalized patients. It is estimated that 7million central venous catheters (CVCs) will be inserted annually in theUnited States. Even with the best available aseptic techniques beingused during insertion and maintenance of the catheter, 1 of every 20CVCs inserted will be associated with at least 1 episode of bloodstreaminfection.

In the early 2000's, an estimated 300,000 cases of catheter-relatedbloodstream infection (CRBSI) occurred in the United States each year.Existing interventions to control CRBSI includeanticoagulant/antimicrobial lock, use of ionic silver at the insertionsite, employment of an aseptic hub model, and antimicrobial impregnationof catheters. However, these solutions have not proven ideal.

Several factors pertaining to the pathogenesis of CRBSI have beenidentified during the last decade. The skin and the hub are the mostcommon sources of colonization of percutaneous vascular catheters. Forshort-term, nontunneled, noncuffed catheters, the organisms migrate fromthe skin insertion site along the intercutaneous segment, eventuallyreaching the intravascular segment or the tip. Thus, it may bebeneficial to include the galvanic release coating(s) described hereinalong any (or all) portions of the catheters that are inserted into thepatient, to allow galvanic release of the antimicrobial ions (e.g.,silver, nickel, etc.) as described above. For example, FIG. 16illustrates one variation of a catheter 1601 (shown as an intravascularcatheter in this example) that has been coated along its length (or overa region) with a layer of the mixture of between about 25% to about 75%(e.g., 30% and 70%) by volume of an anodic metal, and between about 25%to about 75% (e.g., 30% to 70%) by volume of a cathodic metalco-deposited on an outer substrate surface to form a non-uniform mixtureof the anodic and cathodic metals. The coating may comprise a pluralityof microregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal. The anodic metal is galvanically releasedas antimicrobial ions when the apparatus is inserted into a subject'sbody.

Generally, long-term catheters (particularly those that are cuffed orsurgically implanted, such as those illustrated in FIGS. 15A-15B), thehub is a major source of colonization of the catheter lumen, whichultimately leads to bloodstream infections through luminal colonizationof the intravascular segment. Thus, in some variations the hub regionmay be coated as described herein.

In addition to the examples described above, other insertable orimplantable device that may be coated as described herein may includeimplantable devices such as drug delivery devices (e.g., pumps), cardiacmanagement devices (e.g., pacemakers), cochlear implants, analytesensing devices, catheters, cannulas or the like. Essentially anymedical device which experiences microbial colonization and/or biofilmformation and/or encrustation is appropriate for the practice of thepresent invention, including analyte sensing devices such aselectrochemical glucose sensors, drug delivery devices such as insulinpumps, devices which augment hearing such as cochlear implants, urinecontacting devices (for example, urethral stents, urinary catheters),blood contacting devices (including needles, blood bags, cardiovascularstents, venous access devices, valves, vascular grafts, hemodialysis andbiliary stents), and body tissue and tissue fluid contacting devices(including biosensors, implants and artificial organs). Medical devicesinclude but are not limited to permanent catheters, (e.g., centralvenous catheters, dialysis catheters, long-term tunneled central venouscatheters, short-term central venous catheters, peripherally insertedcentral catheters, peripheral venous catheters, pulmonary arterySwan-Ganz catheters, urinary catheters, and peritoneal catheters),long-term urinary devices, tissue bonding urinary devices, vasculargrafts, vascular catheter ports, wound drain tubes, ventricularcatheters, hydrocephalus shunts, cerebral and spinal shunts, heartvalves, heart assist devices (e.g., left ventricular assist devices),pacemaker capsules, incontinence devices, penile implants, small ortemporary joint replacements, urinary dilator, cannulae, elastomers,hydrogels, surgical instruments, dental instruments, tubings, such asintravenous tubes, breathing tubes, dental water lines, dental draintubes, and feeding tubes, fabrics, paper, indicator strips (e.g., paperindicator strips or plastic indicator strips), adhesives (e.g., hydrogeladhesives, hot-melt adhesives, or solvent-based adhesives), bandages,orthopedic implants, and any other device used in the medical field.Medical devices also include any device which may be inserted orimplanted into a human being or other animal, or placed at the insertionor implantation site such as the skin near the insertion or implantationsite, and which include at least one surface which is susceptible tocolonization by biofilm embedded microorganisms. Medical devices alsoinclude any other surface which may be desired or necessary to preventbiofilm embedded microorganisms from growing or proliferating on atleast one surface of the medical device, or to remove or clean biofilmembedded microorganisms from the at least one surface of the medicaldevice, such as the surfaces of equipment in operating rooms, emergencyrooms, hospital rooms, clinics, and bathrooms. Non-implanted devices foruse in a medical procedure that may be coated as described hereininclude surgical tools, e.g., suturing devices, forceps, retractors,sponges, etc.

Orthopedic devices may in particular benefit from the coatings describedherein. An implant as described herein may be used to treat bone and/orsoft tissue. In some variations the implants are bone implantsspecifically, and may be configured to support as well as treat thebone. For example, the implant may be used to secure (as a screw, nail,bolt, clamp, etc.) another member such as a plate, rod, or the like, orthe implant may itself include a support member such as a rod, plate,etc. In some variations, the implant is a soft tissue implant that isconfigured to be secured within non-bone body structures.

For example, FIGS. 17A-17C illustrate one variation of an apparatus foruse in delivering an antimicrobial ion (e.g., silver ions) to a repairsite to prevent or treat infection. In this example, apparatus includesa replaceable/removable insert that is coated. The insert maybe a meshor other material having a relatively large surface to volume ratio(e.g., large surface area). For example, FIG. 17A shows a cannulatedbone screw 1701, e.g., a bone screw having a central cannula region (notvisible in FIG. 17A) into which another device or element may beinserted, such as the bioabsorbable material 1703 (mesh) shown in FIG.17B. In FIG. 17A, the bone screw includes a distal threaded region 1705and a more proximal head 1707. In FIG. 17B the bioabsorbable mesh 1703is coated with the antimicrobial ion releasing coating such as describedherein (e.g., 30% silver/70% platinum) to a thickness of 100microinches. The cannulated bone screw 1701 may also be coated, or maynot be coated. Either before or after inserting the bone screw into thebody, the bioabsorbable insert 1703 may be inserted into the cannula ofthe bone screw 1701. This is illustrated in FIG. 17C. In practice,multiple inserts 1703 may be added to the bone screw device.

In some variations, the bone screw may itself be coated, without the useof an additional element (e.g., a bioabsorbable insert). FIGS. 18A and18B illustrate different variations of implants (e.g., bone screw) thatinclude antimicrobial ion releasing coatings as described herein. InFIG. 18A, the entire bone screw 1801 is coated with an antimicrobial ionreleasing coating comprising a mixture of between about 25% to 75%(e.g., 30% and 70%) by volume of an anodic metal, and between about 25%to 75% (e.g., 30% to 70%) by volume of a cathodic metal co-deposited onthe outer substrate surface to form a non-uniform mixture of the anodicand cathodic metals, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains forming acontinuous path of interconnected veins of anodic metal through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating to the substrate tothe opposite side of the coating (which may be adjacent to thesubstrate). In FIG. 18B, the bone screw apparatus is a screw that hasnot been completely coated, but includes differently coated regions, orregions that are both coated and uncoated. In this example the substrateis the surface of a bone screw having a striated pattern of regions ofcoatings alternating with uncoated regions.

FIGS. 19A-19B illustrate another variation in which the implant isconfigured as an orthopedic device (e.g., bone screw) having extendablemembers that can be extended out of the body of the bone screw toproject into the tissue and allow release of antimicrobial ions into thesurrounding tissue. In this variation, the implant 1901 is configured asa bone screw that is hollow or contains a hollow inner body region (notvisible in FIG. 19A) into which a replaceable/rechargeable treatmentcartridge may be inserted and/or removed. The cartridge may be itselfscrewed into the body, or it may be otherwise secured within the body.The cartridge may include one or more (e.g., a plurality) of ion releasemembers 1909 extending or extendable from the cartridge and thereforethe implant. The ion release member(s) may be configured to releasesilver, zinc or silver and zinc and may be coated with any of thecoatings described herein. In general, an ion release member may beconfigured as an elongate member such as an arm, wire, branch, or thelike. The ion release member may be a coated member such as a Nitinol orother shape-memory member coated with an antimicrobial ion releasingcoating comprising a mixture of between about 25% to about 75% (e.g.,30% and 70%) by volume of an anodic metal (e.g., silver), and betweenabout 25% to about 75% (e.g., 30% to 70%) by volume of a cathodic metal(e.g., platinum) co-deposited on the outer substrate surface to form anon-uniform mixture of the anodic and cathodic metals, wherein thecoating comprises a plurality of microregions or microdomains of anodicmetal in a matrix of cathodic metal or a plurality of microregions ormicrodomains of cathodic metal in a matrix of anodic metal, themicroregions or microdomains forming a continuous path of interconnectedveins of anodic metal through the coating thickness, or a continuouspath of interconnected veins of cathodic metal through the coatingthickness, wherein the continuous path extends from an outer surface ofthe coating to the substrate to the opposite side of the coating (whichmay be adjacent to the substrate). As mentioned, the implant (or thetreatment cartridge portion) may include a plurality of ion releasemembers.

These implants may have one or more exit channels 1905. In general theexit channels may be openings from the inner hollow region (e.g.cannulated body) of the implant through a side wall of the implant andout, possibly in the threaded region 1907. Thus, in FIGS. 19A and 19B,the exit channel is configured to deflect the one or more ion releasemembers away from a long axis of the implant. For example, the exitchannel may be configured to deflect the one or more ion release membersagainst a thread of the outer threaded region so that it deflects awayfrom the implant. In some variations a plurality of exit channelsextending through the cannulated body 1903.

An implant such as the one shown in FIGS. 19A-19B may also include aguide (or guide element, including a rail, keying, etc.) within thechannel configured to guide or direct the one or more ion release memberout of the cannulated body 1903 from the at least one exit channel 1905.The exit channels may be configured to allow tissue (e.g., bone)ingrowth, which may help with stability of the device once implanted.For example, the exit channels may be slightly oversized compared to theion release members, permitting or encouraging in-growth. In somevariations the exit channels may be doped or otherwise include atissue-growth enhancing or encouraging factor (such as a growth factor),or may be otherwise modified to encourage tissue growth.

A treatment cartridge may be replaceable. For example, a treatmentcartridge may be configured to be removable from the cannulated body ofthe implant in situ, without removing the body of the implant from thedevice. Thus, the body of the implant may be structurally supportive(e.g., supporting the bone) while the silver-releasing cartridge armsmay be re-charged by inserting another (replacement) cartridge after theprevious cartridge has corroded. For example, an elongate cannulatedbody 1903 may be configured as bone screw (e.g., an intramedullary bonescrew).

In addition, the antimicrobial coatings described herein may also beeffective for use in non-implantable and/or insertable devices. Asmentioned above, any apparatus that may come into contact with aconductive (e.g., electrolytic) fluid, such as bodily fluids, maybenefited from the antimicrobial coatings described herein; suchapparatuses are not limited to medical devices and systems.

For example, also descried herein are garments (e.g., gloves, masks,scrubs), including facial masks (surgical masks, filters, or the like),sporting equipment (e.g., facemasks, mouthpieces, helmets, etc.), shoes(sole/shoe inserts, etc.), jewelry (necklaces, bracelets, rings, etc.)and the like, that may be coated or may include a coated region, whereinthe coating comprises any of the antimicrobial ion releasing coatingsdescribed herein, such as a coating comprising a mixture of betweenabout 25% to about 75% (e.g., 30% and 70%) by volume of an anodic metal(e.g., silver), and between about 25% to about 75% (e.g., 30% to 70%) byvolume of a cathodic metal (e.g., platinum) co-deposited on the outersubstrate surface to form a non-uniform mixture of the anodic andcathodic metals, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains forming acontinuous path of interconnected veins of anodic metal through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating to the substrate tothe opposite side of the coating (which may be adjacent to thesubstrate).

FIG. 20 is one example of a non-medical application of a coating asdescribed herein. For example, an animal cage 2005 may be coated(particularly on the bottom region) with any of the antimicrobialcoatings described herein. In this example, the cage may include anantimicrobial ion releasing coatings as described herein, such as acoating comprising a mixture of between about 25% to about 75% (e.g.,30% and 70%) by volume of an anodic metal (e.g., silver), and betweenabout 25% to about 75% (e.g., 30% to 70%) by volume of a cathodic metal(e.g., platinum) co-deposited on the outer substrate surface to form anon-uniform mixture of the anodic and cathodic metals, wherein thecoating comprises a plurality of microregions or microdomains of anodicmetal in a matrix of cathodic metal or a plurality of microregions ormicrodomains of cathodic metal in a matrix of anodic metal, themicroregions or microdomains forming a continuous path of interconnectedveins of anodic metal through the coating thickness, or a continuouspath of interconnected veins of cathodic metal through the coatingthickness, wherein the continuous path extends from an outer surface ofthe coating to the substrate to the opposite side of the coating (whichmay be adjacent to the substrate).

Similarly, any household apparatus that may be exposed to a bodily fluid(including sweat and/or mucus, as from sneezing or coughing) may becoated with any of the coatings described herein, to act as an effectiveantimicrobial barrier. For example, FIG. 21 illustrates a doorknob 2101that may be partially or completely coated with any of the antimicrobialion releasing coatings described herein on a portion that will be heldby an operator's hand 2109. Thus, this region may be coated with acoating comprising an antimicrobial ion releasing coating such as acoating comprising a mixture of between about 25% to about 75% (e.g.,30% and 70%) by volume of an anodic metal (e.g., silver), and betweenabout 25% to about 75% (e.g., 30% to 70%) by volume of a cathodic metal(e.g., platinum) co-deposited on the outer substrate surface to form anon-uniform mixture of the anodic and cathodic metals, wherein thecoating comprises a plurality of microregions or microdomains of anodicmetal in a matrix of cathodic metal or a plurality of microregions ormicrodomains of cathodic metal in a matrix of anodic metal, themicroregions or microdomains forming a continuous path of interconnectedveins of anodic metal through the coating thickness, or a continuouspath of interconnected veins of cathodic metal through the coatingthickness, wherein the continuous path extends from an outer surface ofthe coating to the substrate to the opposite side of the coating (whichmay be adjacent to the substrate). Other household fixtures that may bereadily coated include light switches, door handles/pulls, kitchenappliances (and particularly handles/controls for kitchen appliances),tabletop and/or countertop surfaces, and bathroom surfaces. For example,a toilet handle, toilet (including toilet seat and/or bowl), sink,and/or faucet may be coated as described herein.

In addition, cookware, dining wear, and/or cutlery may be coated. Suchcoatings are safe, and non-toxic, though still antimicrobial, and may beextremely long lasting (e.g., extending over months or years, dependingon coating thicknesses and use). Further, these coatings do not degradeor lose their antimicrobial activity, which is dependent primarily orexclusively on the galvanic release of ions (e.g., silver ions). Forexample, as shown in FIGS. 22A-22B, cutlery (e.g., spoons 2205, forks2207, etc.) may be coated as described herein, particularly on theportions to be placed in a user's mouth. FIG. 22B shows an example of aninfant spoon 2205′ having an elongate handle and end region 2230 formingthe spoon that is to be placed in an infant's mouth; this end region2230 may be coated specifically, e.g., with an antimicrobial ionreleasing coating as described herein, such as a coating comprising amixture of between about 25% to about 75% (e.g., 30% and 70%) by volumeof an anodic metal (e.g., silver), and between about 25% to about 75%(e.g., 30% to 70%) by volume of a cathodic metal (e.g., platinum)co-deposited on the outer substrate surface to form a non-uniformmixture of the anodic and cathodic metals, wherein the coating comprisesa plurality of microregions or microdomains of anodic metal in a matrixof cathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of anodic metal, the microregions ormicrodomains forming a continuous path of interconnected veins of anodicmetal through the coating thickness, or a continuous path ofinterconnected veins of cathodic metal through the coating thickness,wherein the continuous path extends from an outer surface of the coatingto the substrate to the opposite side of the coating (which may beadjacent to the substrate). The substrate may be stainless steel,polymer, or any other appropriate material. The coating is both washableand sterilizable without losing efficacy.

In some variations, the substrate is a particle, such as a micro (ornano) particle that is coated as described herein, to form a powder orother material that may be added to a device or system to provideantimicrobial activity. For example, polymeric particles may be coated(or a polymeric material may be coated and ground/broken up into smallerparticles) with any of the antimicrobial ion releasing coatingsdescribed herein, such as a coating comprising a mixture of betweenabout 25% to about 75% (e.g., 30% and 70%) by volume of an anodic metal(e.g., silver), and between about 25% to about 75% (e.g., 30% to 70%) byvolume of a cathodic metal (e.g., platinum) co-deposited on the outersubstrate surface to form a non-uniform mixture of the anodic andcathodic metals, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains forming acontinuous path of interconnected veins of anodic metal through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating to the substrate tothe opposite side of the coating (which may be adjacent to thesubstrate). The resulting particles (which may be referred to as anantimicrobial powder) may be added, e.g., into structures or ontosurfaces that will come into contact with bodily fluids.

Surface Treatments

As mentioned above, the antimicrobial coatings described herein may beapplied directly to any appropriate substrate; the substrate may, insome variations, form a part of another device or system that comes intocontact with a bodily fluid and therefore benefits from the use of theseantimicrobial coatings. For example, a coating may be made directly ontothe substrate, or it may be made onto another coating (e.g., a primercoating) which may be made to prepare the substrate for the coating.Examples of primer coatings are adhesion coatings, which may include atitanium and/or tantalum undercoating, as described above.

In some variations, the material is pretreated to prepare the surface toreceive the coating. For example, in some metals (e.g., nickel titanium,stainless steel, etc.) the surface may oxidize naturally, and it may bebeneficial to remove this oxide layer prior to applying theantimicrobial coatings described herein. For example, a substrate may beprepared by removing an oxide layer (or for other reasons) by vacuumblast cleaning with a noble gas such as argon (e.g., argon blasting orargon blast cleaning under a vacuum). Removing the thin outer oxidelayer may enhance adhesion of the coating. In general, vacuum cleaningmay be helpful, and may be performed immediately before applying thecoating (e.g., co-sputtering the anodic and cathodic materials).

Other useful pre-treatments may include applying an undercoating layer(e.g., of platinum, parylene, etc.). Such undercoatings may be appliedfirst (e.g., by sputter deposition, etc.).

One additional benefit of the coatings described herein is that they maybe applied in a relatively cool application process, e.g., in which thetemperature at which the co-deposition of the anodic material andcathodic material is applies is relatively cool (e.g., less than 150°C., less than 120° C., less than 100° C., less than 90° C., less than80° C., less than 70° C., less than 60° C., less than 50° C., etc.). Thetemperature of application may be adjusted along with the time to formthe coating (e.g., cooler application may generally take longer). Coolerapplication may be particularly beneficial when the substrates to whichit is being applied is temperature sensitive, or when it is beingapplied to a device (including devices having active/electronic parts)that are rate below a predetermined temperature.

Post-Coating Treatments

Any of the apparatuses described herein (e.g., any of the coatingsdescribed herein) maybe treated to enhance the galvanic release ofantimicrobial ions (e.g., silver). Such treatments may be referred to aspost-coating treatments because they may be performed after the coatinghas been applied. For example, any of the apparatuses described hereinmay include coatings that are treated to enhance the surface area bycracking, fracturing, or otherwise roughening the coating, which mayincrease the exposed surface area of the coating. Another post-coatingtreatment is the application of ozone (ozonation) as described in moredetail and illustrated below.

Post-coating treatments may include thermal treatments (e.g., exposingthe surface to a cooler temperature to crack or fracture the coating),and/or energy (e.g., ultrasound, RF, etc.) to fracture the surface. Forexample, in some variations the coating may be connected to anoscillating high voltage source that makes cracks in the coating. Forexample, FIG. 23A and 23B illustrates a variation of a substrate 2320(similar to the example shown in FIGS. 2A-2D) has been coated with anantimicrobial ion releasing coating 2300 as described above. In thisexample, after co-depositing the anodic and cathodic metals, the coatedapparatus has been treated to fracture the coating, formingbreaks/fractures 2350 (shown schematically in FIG. 23B from the enlargedregion B in FIG. 23A). In this example, the fractures 2350 are formedvertically into the coating to expose more of the anodic metal andcathodic metal, potentially allowing for greater (and/or faster) releaseof anodic antimicrobial ions.

Thus, in any of the apparatuses described herein, the coatings may befractured (cracked, etc.) to enlarge the surface area. Cracks orfractures may be formed of a predetermined density and/or depth. Forexample, the coating may be fractured or may include cleavage regionsinto the thickness of the coating at a density of between 0.01% and 80%of the surface (e.g., greater than 0.1%, greater than 1%, greater than5%, greater than 10%, greater than 15%, etc.). The percentage offracturing typically results in an increase the in the surface area, andmay therefore be referred to as a percentage increase in the surfacearea. For example the percent increase in the surface area due tofracturing the surface may result in an increase of greater than 0.25times the un-fractured surface area (e.g., a 25% or greater surface areafollowing fracturing). In some variations the surface area may beincreased greater than 0.3 times (e.g., 0.35× or greater, 0.40× orgreater, 0.45× or greater, 0.5× or greater, 0.6× or greater, 0.75× orgreater, 0.8× or greater, 0.9× or greater, 1× or greater, 2× or greater,3× or greater, etc.).

Ozone

As mentioned above, any of the coatings (or solid substrates, e.g.,solid silver substrates) described herein may be treated with ozone,which will generally greatly enhance the antimicrobial effects.

For example, FIG. 24 illustrates one method of forming an apparatusincluding an ozonated surface coating. In FIG. 24, an optional step ofpretreating/preparing a substrate surface (e.g., by cleaning it withargon gas preparation and/or applying an adhesion layer, as describedabove) may be used 2401. Thereafter the substrate surface may be coatedwith silver or a coating of co-deposited silver/cathodic material (e.g.,25%-75% anodic silver), where the remainder is mostly the cathodicmetal) 2403. Optionally, the surface may be further treated by, e.g.,cracking 2405, as described above. Finally, the surface may be treatedwith ozone 2407. For example, the surface may be treated by applying ajet of gas including ozone (e.g., oxygen gas) to/against the surface.

FIGS. 25-28B illustrate by comparison some of the effects of ozonationon substrates including examples of the substrates described herein,although the same results (showing robust enhancement of theantimicrobial effect of the anion, e.g., silver, following ozonation).

For example, FIG. 25 illustrates the enhancement of antimicrobialacitivty in a silver wire (pieces of solid silver wire) with 2505 andwithout 2509 ozonation. In this example, even with pure silver anantimicrobial effect is seen, as made apparent by the clearing regions2507 around the ozonated silver wire pieces in the top of the figure, incontrast to the non-ozonated silver wire pieces 2509 in the bottom. Inthis example, the elemental silver (wire) is exposed to ozone, which maycreate complexes that allow for formation of the clearings; zones ofinhibition where the silver wire is exposed to a liquid (such as agrowth media in this example). For implantable devices, the surface(s)of the devices may be coated or plated with silver (or any of thecoatings described herein), e.g., via vapor deposition or plating, andsubsequently the coating may be exposed to ozone for a period of time tocreate silver complexes having antimicrobial activity. Thus, althoughthe majority of these example shown herein are silver-containingcoatings, with respect to FIG. 24, any of these methods (e.g.,enhancement of antimicrobial activity due to ozonation of the silver)may be used.

FIGS. 26-28B illustrate the use of ozonation to enhance antimicrobialeffects. For example, in FIG. 26, two pairs of otherwise-identicalimplants (silver-ion releasing implants) coated with a layer ofco-deposited silver and platinum (cathodic metal) are cultured withbacteria to determine the effect of ozonation. In this figure, theimplants on the left and right 2605 are treated by blowing in a streamof ozone for greater than 5 minutes, in contrast to the coated implantson the top and bottom 2609. After culturing with bacterial for 24 hrs(or more) there are distinct clearing regions 2607 (antibacterialregions) around the ozonated implants that are substantially larger(greater than 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, 100%, 2×, 3×, 4×,5×, 6×, etc.) than the non-ozonated implants that are otherwiseidentical. The size of the clearing region may be dependent upon thelength of the application of ozone, although this relationship may belimited (e.g., may reach a plateau, e.g., beyond a certain time period).

Similarly, FIGS. 27 and 28A-28B also illustrate the general principlesdescribed above, e.g., enhancement of antimicrobial activity bypre-treatment with ozone for greater than 5 minutes. In FIG. 27, sampleof bioabsorbable mesh 2705 has been coated with a co-deposited silverand cathodic material as described herein, and treated by exposure ofozone for greater than 15 minutes (e.g., greater than 5 min), resultingin clearing regions 2707. In contrast a similar piece of mesh withoutany coating 2709 shows overgrowth of the bacterial in the culture dish.Similarly, FIGS. 28A and 28B illustrate the use of ozonation to increasethe antibacterial effects; in FIGS. 27, and 28A-28B, similar meshes,coated by a co-deposition of silver and platinum are exposed to ozonefor different times, and shown approximately increasing enhancement ofthe antibacterial effects (as measurable by the size of the bacterialclearing in the test). For example, in FIG. 28A, similar pieces of meshare used to example different exposure times to the ozone (in general,the shortest exposure time of the ozone 2804 has a smaller clearingrelative to the increasing exposures to ozone 2805, 2806, 2807).

Another example (not shown) of ozone treatment was used to confirm thatthe mesh (such as the mesh shown in FIGS. 28A-28B) when coated withsilver/platinum matrix as described above could result in enhancedantimicrobial activity. In this example, a double sided mesh substratewas coated with a co-deposition of Ag/Pt matrix (as described above) andozone-treated. The mesh is a bioabsorbable knitted mesh. A 40×10 mmpiece of coated and ozone-treated knitted mesh was placed into amicrocentrifuge tube containing 300 μL Tryptic Soy Broth (TSB). The tubeand a control tube containing 300 μL TSB was inoculated withStaphylococcus aureus at a concentration of 2.97×10⁵ CFU/mL. After 24hours, a count for viable bacteria in the ozone-treated tube and acontrol tube (in which the mesh was coated but not ozonated) wasperformed and counted. The results showed zero (0) Colony FormingUnits/mL of S. aureus for the ozone-treated coated mesh, and 1.85×10⁹Colony Forming Units/mL of S. aureus for the non-ozone treated coatedmesh (where the limit of detection for this example is 100 CFU/mL andreported data is <100 CFU/mL when 0 colonies are observed).

When a feature or element is herein referred to as being “on” anotherfeature or element, it can be directly on the other feature or elementor intervening features and/or elements may also be present. Incontrast, when a feature or element is referred to as being “directlyon” another feature or element, there are no intervening features orelements present. It will also be understood that, when a feature orelement is referred to as being “connected”, “attached” or “coupled” toanother feature or element, it can be directly connected, attached orcoupled to the other feature or element or intervening features orelements may be present. In contrast, when a feature or element isreferred to as being “directly connected”, “directly attached” or“directly coupled” to another feature or element, there are nointervening features or elements present. Although described or shownwith respect to one embodiment, the features and elements so describedor shown can apply to other embodiments. It will also be appreciated bythose of skill in the art that references to a structure or feature thatis disposed “adjacent” another feature may have portions that overlap orunderlie the adjacent feature.

Terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.For example, as used herein, the singular forms “a”, “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, steps, operations, elements, components, and/orgroups thereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items and may beabbreviated as “/”.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

Although the terms “first” and “second” may be used herein to describevarious features/elements, these features/elements should not be limitedby these terms, unless the context indicates otherwise. These terms maybe used to distinguish one feature/element from another feature/element.Thus, a first feature/element discussed below could be termed a secondfeature/element, and similarly, a second feature/element discussed belowcould be termed a first feature/element without departing from theteachings of the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising” means various components can be co-jointlyemployed in the methods and articles (e.g., compositions and apparatusesincluding device and methods). For example, the term “comprising” willbe understood to imply the inclusion of any stated elements or steps butnot the exclusion of any other elements or steps.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical rangerecited herein is intended to include all sub-ranges subsumed therein.

Although various illustrative embodiments are described above, any of anumber of changes may be made to various embodiments without departingfrom the scope of the invention as described by the claims. For example,the order in which various described method steps are performed mayoften be changed in alternative embodiments, and in other alternativeembodiments one or more method steps may be skipped altogether. Optionalfeatures of various device and system embodiments may be included insome embodiments and not in others. Therefore, the foregoing descriptionis provided primarily for exemplary purposes and should not beinterpreted to limit the scope of the invention as it is set forth inthe claims.

The examples and illustrations included herein show, by way ofillustration and not of limitation, specific embodiments in which thesubject matter may be practiced. As mentioned, other embodiments may beutilized and derived there from, such that structural and logicalsubstitutions and changes may be made without departing from the scopeof this disclosure. Such embodiments of the inventive subject matter maybe referred to herein individually or collectively by the term“invention” merely for convenience and without intending to voluntarilylimit the scope of this application to any single invention or inventiveconcept, if more than one is, in fact, disclosed. Thus, althoughspecific embodiments have been illustrated and described herein, anyarrangement calculated to achieve the same purpose may be substitutedfor the specific embodiments shown. This disclosure is intended to coverany and all adaptations or variations of various embodiments.Combinations of the above embodiments, and other embodiments notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description.

What is claimed is:
 1. A method of forming an enhanced antimicrobialsurface, the method comprising: co-depositing a coating of silver and acathodic metal onto a substrate surface, wherein the co-depositedcoating comprises a mixture of between about 25% and 75% by volume ofsilver, and between about 25% to 75% by volume of the cathodic metal;and applying ozone to the coated surface for at least 5 minutes.
 2. Themethod of claim 1, further comprising blasting the substrate surfacewith a noble gas or charged noble gas before applying the silvermaterial.
 3. The method of claim 1, further comprising blasting thesubstrate surface with argon before applying the silver metal.
 4. Themethod of claim 1, wherein coating comprises coating the substratesurface with a silver material comprising a mixture of between about 25%and 75% by volume of silver, and between about 25% to 75% by volume of acathodic metal co-deposited on the substrate so that the coatingcomprises a plurality of microregions or microdomains of the silver in amatrix of cathodic metal or a plurality of microregions or microdomainsof cathodic metal in a matrix of silver, the microregions ormicrodomains forming a continuous path of interconnected veins of silverthrough the coating thickness, or a continuous path of interconnectedveins of cathodic metal through the coating thickness, wherein thecontinuous path extends from an outer surface of the coating through thecoating to an opposite side of the coating.
 5. The method of claim 1,wherein applying ozone to the coated surface for at least 5 minutescomprises applying the ozone for at least 10 minutes.
 6. The method ofclaim 1, wherein applying the ozone comprises spraying the surface witha jet comprising ozone.
 7. A method of galvanically releasingantimicrobial ions to form an antimicrobial zone around a surface of asubstrate, the method comprising: contacting the surface with aconductive fluid, wherein the surface comprises a coating comprising amixture of between about 25% and 75% by volume of silver, and betweenabout 25% to 75% by volume of a cathodic metal co-deposited on thesubstrate, further wherein the coating has been ozonized by theapplication of ozone to the surface for at least 5 minutes; andgalvanically releasing antimicrobial ions of the anodic metal from thecoating.
 8. The method of claim 7, wherein the coating comprises aplurality of microregions or microdomains of the silver in a matrix ofcathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of silver, the microregions or microdomainsforming a continuous path of interconnected veins of silver through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating through the coating toan opposite side of the coating.
 9. An apparatus that galvanicallyreleases antimicrobial ions, the apparatus comprising: a substratesurface; and an ozonated coating on the outer substrate surface, theozonated coating comprising a mixture of between about 25% and 75% byvolume of silver, and between about 25% to 75% by volume of a cathodicmetal co-deposited on the substrate surface, so that there is acontinuous path of silver from the surface to the outer substratesurface.
 10. The apparatus of claim 9, wherein the ozonated coatingcomprises Ag₄O₄.
 11. The apparatus of claim 9, wherein, in the ozonatedcoating, less than 30% of the silver is fully encapsulated within thematrix of cathodic metal and connects through a microregion ormicrodomain of silver to the outer surface of the coating.
 12. Theapparatus of claim 9, wherein, in the ozonated coating, less than 20% ofthe silver is fully encapsulated within the matrix of cathodic metal andconnects through a microregion or microdomain of silver to the outersurface of the coating.
 13. The apparatus of claim 9, wherein thecathodic metal comprises one or more of: palladium, platinum, or gold.14. The apparatus of claim 9, wherein the cathodic metal comprises oneor more of: palladium, platinum, gold, molybdenum, titanium, iridium,osmium, niobium and rhenium.
 15. The apparatus of claim 9, wherein theozonated coating comprises the silver and the cathodic metal that havebeen vapor-deposited onto the length of a filament so that the silver isnot encapsulated by the cathodic metal.
 16. The apparatus of claim 9,wherein the substrate surface is an outer surface of one of: apacemaker, defibrillator, neurostimulator, or ophthalmic implant. 17.The apparatus of claim 9, wherein the substrate surface is an outersurface of one of: an implantable shunt, an artificial joint, a hipimplant, a knee implant, a catheter, a stent, an implantable coil, apump, an intrauterine device (IUD), a heart valve, a surgical fastener,a surgical staple, a surgical pin, a suture, a surgical screw, animplantable electrical lead, or an implantable plate.
 18. The apparatusof claim 9, wherein the substrate surface is an outer surface of one of:a retractor, a bariatric balloon, an orthodontic brace, a breastimplant, a surgical sponge, a gauze, a mesh, a mesh pouch, or a woundpacking material.
 19. The apparatus of claim 9, wherein the ozonatedcoating is fractured.
 20. The apparatus of claim 9, wherein the ozonatedcoating is fractured so that a surface area of the coating is increasedby at least 25% compared to the surface area of the coating in anunfractured state.
 21. The apparatus of claim 9, wherein the substrateis a bioabsorbable filament.
 22. The apparatus of claim 9, wherein thesubstrate is a bioabsorbable filament comprise one or more of:polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA),polyglycolide (PGA), polyglycoside-co-trimethylene carbonate (PGTMC),poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), andpoly(caprolactone) (PCL).
 23. An apparatus that galvanically releasesantimicrobial ions, the apparatus comprising: a substrate surface; andan ozonated coating on the outer substrate surface, the ozonated coatingcomprising a mixture of between about 25% and 75% by volume of silver,and between about 25% to 75% by volume of a cathodic metal co-depositedon the substrate surface, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains forming acontinuous path of interconnected veins of anodic metal through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating through the coating toan opposite side of the coating.
 24. The apparatus of claim 23, whereinthe ozonated coating comprises Ag₄O₄.
 25. The apparatus of claim 23,wherein, in the ozonated coating, less than 30% of the silver is fullyencapsulated within the matrix of cathodic metal and connects through amicroregion or microdomain of silver to the outer surface of thecoating.
 26. The apparatus of claim 23, wherein the cathodic metalcomprises one or more of: palladium, platinum, or gold.
 27. Theapparatus of claim 23, wherein the cathodic metal comprises one or moreof: palladium, platinum, gold, molybdenum, titanium, iridium, osmium,niobium and rhenium.
 28. The apparatus of claim 23, wherein the ozonatedcoating comprises the silver and the cathodic metal that have beenvapor-deposited onto the length of a filament so that the silver is notencapsulated by the cathodic metal.
 29. The apparatus of claim 23,wherein the coating is fractured.
 30. The apparatus of claim 23, whereinthe coating is fractured so that a surface area of the coating isincreased by at least 25% compared to the surface area of the coating inan unfractured state.